M Jeffrey, Assistant Professor
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5R01MH085298-02 from National Institute Of Mental Health
Abstract: Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight. Our recent work also demonstrates antidepressant-like behavioral effects of ghrelin. As such, ghrelin levels rise not only in association with hunger and fasting, thus leading to stimulation of food intake and conservation of energy stores, but also upon chronic stress. These elevations with stress seem to minimize the depression-like behaviors normally associated with stress, as acute peripheral infusions of ghrelin into wild-type mice induce antidepressant-like behaviors, and as mice lacking ghrelin receptors (growth hormone secretagogue receptor; GHSR) demonstrate even more depression-like behaviors than wild-type mice. Ghrelin rises also mediate the antidepressant-like effects of prolonged caloric restriction. These ghrelin effects presumably occur via interaction with its receptors in one or more of the CNS sites comprising GHSR´s well-defined, discrete pattern of expression. For instance, GHSRs are expressed within dopaminergic ventral tegmental area (VTA) neurons that are involved in brain reward circuits and that also play an obligatory role in the development of rodent measures of depression. GHSRs also are highly expressed within the hippocampus, another site with well established effects on mood and antidepressant efficacy. In the current application, we provide studies designed to further explore ghrelin´s actions in promoting antidepressant-like behaviors. We will investigate the effects of chronic ghrelin administration and pharmacologic blockade of ghrelin action on these behaviors in both male and female mice. We will employ unique genetically-manipulated mouse models in which GHSR expression can be site-selectively targeted to or deleted from dopaminergic VTA neurons or hippocampal neurons as well as CNS site-specific ghrelin microinjection studies to determine the role of the VTA and hippocampus in ghrelin´s antidepressant effects. Finally, we will further explore the mechanism of ghrelin´s antidepressant actions by examining the role of brain derived nuclear factor (BDNF) signaling cascades within both VTA and hippocampal circuits. We hope that these studies will uncover new pathways involved in the development of mood disorders, including the depression so closely linked to conditions with known perturbations of ghrelin physiology. The experiments proposed in this study have been designed to investigate the role ghrelin plays in mood and the responses to chronic stress. It is hoped that these studies will uncover new pathways involved in the development of depression and will result in new therapies to treat mood disorders, and particularly the depression so closely linked to chronic stress and conditions with known perturbations of ghrelin physiology
Keywords: Acute; Affective Disorders; Ammon Horn; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Behavior; Behavioral; biological signal transduction; Body Weight; Brain; Caloric Restriction; calorie restriction; Cell Communication and Signaling; Cell Signaling; Chemotherapy-Hormones/Steroids; Chronic; Chronic stress; Cornu Ammonis; Dentate Fascia; dentate gyrus; Dentate Gyrus; Depression; deprived of food; design; designing; Development; Eating; Encephalon; Encephalons; Endocrine Gland Secretion; experiment; experimental research; experimental study; Fascia Dentata; fasted; Fasting; fasts; Female; Food Deprivation; Food deprivation (experimental); Food Intake; Genetic; ghrelin; ghrelin receptor; GHS receptor type 1; growth hormone secretagogue receptor; growth hormone secretagogue receptor type 1; Gyrus Dentatus; heavy metal lead; heavy metal Pb; hippocampal; Hippocampus; Hippocampus (Brain); Hormones; Hunger; Infusion; Infusion procedures; Injection of therapeutic agent; Injections; Intracellular Communication and Signaling; Ion Channels, Potassium; K channel; Lead; Link; male; Mammals, Mice; Mammals, Rodents; Measures; Mediating; Mental Depression; Methods; Mice; Microinjections; Modeling; Mood Disorders; Moods; mouse model; Murine; Mus; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; neuronal; Neurons; Nuclear; pathway; Pathway interactions; Pattern; Pb element; Peripheral; Physiologic; Physiological; Physiology; Play; Potassium Channel; public health relevance; receptor; Receptor Protein; Research Design; research study; response; Rewards; Rodent; Rodentia; Rodentias; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; social; Social isolation; social role; Stress; Structure of dentate gyrus; study design; Study Type; subcutaneous; System; System, LOINC Axis 4; Therapeutic Hormone; Ventral Tegmental Area; ventral tegmentum; Wild Type Mouse; Work
Relevance: The experiments proposed in this study have been designed to investigate the role ghrelin plays in mood and the responses to chronic stress. It is hoped that these studies will uncover new pathways involved in the development of depression and will result in new therapies to treat mood disorders, and particularly the depression so closely linked to chronic stress and conditions with known perturbations of ghrelin physiology
Project start date: 2010-04-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01MH085298-02 (2011): $356625
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to M Jeffrey
CAUSAL MEDIATION ANALYSIS OF DENTAL CARIES IN VLBW AND BPD ADOLESCENTS
M Jeffrey, Assistant Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 5R03DE018391-02 from National Institute Of Dental & Craniofacial Research
Abstract: Very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) are significant health issues which are also risk factors for oral health disease, including dental caries. In addition, VLBW/BPD is associated both with enamel defects, a biological risk factor for caries, and reduced cognitive development which may hinder the acquisition of healthy oral health behavior. Furthermore, both VLBW and BPD disproportionately affect minorities and those with low SES. The relative contributions or
Keywords: This project seeks to learn about the reasons (whether they are biologic, oral health behavioral, or both) for the increased risk of dental caries among adolescents with very low birth weight (VLBW) and/or bronchopulmonary dysplasia (BPD). Our specific goals are to develop new statistical methods to handle complex causal models and to use these methods to analyze data from a cohort of adolescents followed from birth. By understanding the mechanisms leading to dental caries in VLBW/BPD children, we can more effectively intervene to improve the oral and general health of these special needs children
Relevance: mediating effects´ of the various biologic, cognitive/behavior and psychosocial factors to the incidence and progression of oral disease in VLBW/BPD individuals is poorly understood. We propose to develop a new approach to mediation analysis and to analyze data from a unique cohort study to help illuminate the relationship between VLBW/BPD and dental caries. Our data are from a study which collected dental caries, enamel defects and oral health behavior information on a cohort of 302 adolescents previously assessed on medical, cognitive, and psychosocial outcomes at birth and at eight years of age. We propose a flexible new statistical method which translates and elaborates a proposed causal diagram into a system of easily fitted generalized linear models. This general context will allow us to incorporate specialized models, such as the zero-inflated Poisson, for the DMFT/S and other dental caries outcomes. We use a potential outcomes framework to develop mediation measures which may be expressed as functions of parameters from our general model. An additional aim of our project is to conduct simulation studies to examine the bias and efficiency of our mediation effect estimators, with a focus on robustness to model departures. Our development and study of methods for mediation analysis will facilitate their broad applicability for dental health and other studies. By helping to illuminate causal mechanisms in the relationship between VLBW/BPD and adolescent dental caries, we also hope to contribute to the development of effective new intervention programs for these special needs children. This project seeks to learn about the reasons (whether they are biologic, oral health behavioral, or both) for the increased risk of dental caries among adolescents with very low birth weight (VLBW) and/or bronchopulmonary dysplasia (BPD). Our specific goals are to develop new statistical methods to handle complex causal models and to use these methods to analyze data from a cohort of adolescents followed from birth. By understanding the mechanisms leading to dental caries in VLBW/BPD children, we can more effectively intervene to improve the oral and general health of these special needs children
Project start date: 2009-04-05
Project end date: 2012-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2012
PFA/PA: EXPANDING ANTIMICROBIAL STEWARDSHIP FOR LONG TERM CARE FACILITY PATIENTS:IMPLEMEN
M Jeffrey
Ohio State Universitycity: Columbus country: United States (us)
Grant 5K23AG038351-02 from National Institute On Aging
Abstract: This proposal represents a five-year curriculum and research plan designed to transition the candidate to an independent investigator in clinical research. During the five years the candidate will complete coursework relevant to the project and will execute the research plan. Infection is one of the leading causes of morbidity and mortality in residents of long-term care facilities (LTCFs). As a result, LTCF residents are exposed to large numbers of antimicrobial agents but use of antimicrobials in LTCF residents is often suboptimal due to difficulty in distinguishing acute infection from colonization and due to the increased likelihood of inaccurate or inappropriate antibiotic prescribing in LTCF residents (for example due to increased presence of antimicrobial resistance). The emergency department (ED) is a common site for treatment of infection in LTCF residents, particularly those most severely ill. Comprehensive programs to address problems of antimicrobial use for LTCF residents in the ED are currently lacking. The conceptual framework for the study is borrowed from the literature on antimicrobial stewardship programs (ASPs), empiric antibiotic treatment, and LTCF infection control guidelines. ASPs have been successfully implemented in inpatient populations to improve antimicrobial prescribing practices and outcomes with resulting decreases in resistance and side effects. This study expands their use to a high-risk ED population with the goal of incorporating both improved diagnostic accuracy and empiric antimicrobial prescribing. Current LTCF infection control guidelines recommend that acute infection be diagnosed in LTCF patients only when they meet specific criteria in order to differentiate active infection from colonization and prevent overuse of antibiotics. These guidelines were developed for use in the LTCFs themselves and have not yet been studied in the ED or inpatient settings. As failure to differentiate acute infection from colonization in the ED may lead to inappropriate antibiotic use, validating diagnostic guidelines in the ED setting is an important step towards appropriate antimicrobial stewardship. Another key concept of these studies is efficiency, driven primarily by Health Information Technology (HIT). In an era of limited resources utilizing pre-existing HIT systems and information will allow extension of ASPs to novel clinical settings and populations. The majority of moderately- to severely-ill LTCF patients receive their initial diagnosis and initiation of antimicrobials in the ED. To improve care of this high-risk population, our overall objective is to develop and implement an antimicrobial stewardship program (ASP) based on use of health information technology (HIT) for ED LTCF patients that will result in improvements both in accuracy of diagnosis and in correct antimicrobial prescribing. To achieve this objective, we will conduct two projects with the following Specific Aims Specific Aim 1 (ED-observational) To develop a validated definition for acute infection and to identify antimicrobial stewardship needs in ED LTCF patients. Specific Aim 2 (ED-interventional) To test the effect of implementing a health information technology (HIT)-based ASP for ED-LTCF patients on diagnosis and treatment of acute infection. For Specific Aim 1, the project (SA1 ED-observational) will consist of a prospective observational cohort study of ED LTCF patients. It will be used to validate definitions for the presence of acute infection in ED LTCF patients (as distinct from colonization), establish baseline rates of need for ASP interventions, and develop data required to construct specific antimicrobial recommendations and an ASP for ED LTCF patients. For Specific Aim 2, a prospective, interventional trial (SA 2 ED-interventional) will be conducted in which an ASP program tailored to ED LTCF patients will be devised and implemented. This phase will rely on the use of a real-time web-based health information technology (HIT) decision support tool to provide the intervention. It will include factors such as the suggested algorithms for diagnosing an acute infection in LTCF patients, a newly developed antibiotic by site grid, patient specific past culture results, patient specific data on hepatic and renal function with recommended dosing, and formulary restrictions. Outcomes will include accuracy of diagnosis, appropriateness of empiric antibiotics, and ongoing requirements for ASP intervention. The career development plan will include didactic work in advanced biostatistical techniques useful in conducting these studies. Coursework will also be undertaken in specific aspects of aging studying biology of aging and challenges in aging research. It will also include a significant component studying the application of health information technology including didactic coursework, online coursework, and practical experience to allow completion of the proposed research and position the candidate for further studies. Based on the results achieved, it will be possible to develop validated and reproducible interventions to improve antimicrobial stewardship in a variety of settings. The proposed projects and career development plan will provide an important initial step towards the ultimate goal of improving care for residents of LTCFs. This research addresses antimicrobial stewardship in nursing home patients, an important means of combating antimicrobial resistance which is a significant and increasing threat to public health. By developing novel technology-based techniques to improve information available and provide decision support to physicians in emergency department the project will ultimately improve accuracy of antibiotic treatment in elders
Keywords: Accident and Emergency department; Acute; Address; Adverse effects; Aging; Agreement; Algorithms; Antibiotic Therapy; Antibiotics; antimicrobial; antimicrobial drug; Antimicrobial Resistance; base; Biology of Aging; career development; Caring; Chronic; Clinical; Clinical Research; clinically significant; Cohort Studies; combat; Data; design; Development Plans; Diagnosis; Diagnostic; diagnostic accuracy; Dose; Educational Curriculum; Elderly; Ensure; experience; Failure (biologic function); Formularies; Functional disorder; Goals; Guidelines; health information technology; Hepatic; high risk; improved; Infection; Infection Control; Information Systems; Inpatients; Intervention; intervention program; Kidney; Lead; Literature; Long-Term Care; meetings; microorganism; Morbidity - disease rate; Mortality Vital Statistics; new technology; novel; Nursing Homes; Online Systems; Outcome; Patients; Pharmacists; Phase; Physicians; Population; Positioning Attribute; prevent; programs; prospective; public health medicine (field); public health relevance; Recommendation; Renal function; Research; Research Personnel; Resistance; Resources; Site; Techniques; Testing; Time; tool; treatment site; Work
Relevance: Public Health Relevance This research addresses antimicrobial stewardship in nursing home patients, an important means of combating antimicrobial resistance which is a significant and increasing threat to public health. By developing novel technology-based techniques to improve information available and provide decision support to physicians in emergency department the project will ultimately improve accuracy of antibiotic treatment in elders
Project start date: 2010-09-30
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-AG-10-011
5K23AG038351-02 (2011): $140452
NEURODEVELOPMENTAL PERSPECTIVES ON ADHD
M Jeffrey
Queens Collegecity: Flushing country: United States (us)
Grant 5R01MH068286-08 from National Institute Of Mental Health
Abstract: This competitive renewal application is based on a novel model which posits that partially distinct neural and cognitive mechanisms are involved in the etiology and developmental trajectory of attention-deficit/hyperactivity disorder (ADHD). We hypothesize that ADHD is due to a primary deficit in regulatory functions, most probably of subcortical origin, that is present early in ontogeny, remains relatively static throughout the lifetime, and is unrelated to the commonly-present, although highly variable, diminution of symptoms and impairment often seem over development. We hypothesize that the variation in diminution of symptoms and impairment frequently seen throughout development is in part related to the degree to which cortically-mediated neural systems can compensate for these early deficits through the use of "top-down" executive control. Using a large sample of "hyperactive/inattentive" and typically-developing control children who were recruited when they were 3-4 years-old and evaluated annually since then, this study will examine trajectories of ADHD symptoms over the school-age years to determine the relationship between changes in ADHD severity and the development of regulatory and executive functions over time. Children will be comprehensively reevaluated annually using clinical and neuropsychological measures between the ages of 8 and 12 years. In addition, these annual assessments will be supplemented by semi-annual parent and teacher ratings of ADHD symptom severity and impairment in the home and school settings, which will greatly facilitate our ability to conduct analyses of individualized trajectories for ADHD severity. The primary aim of the proposed project is to test the hypothesis that the diminution of ADHD symptoms typically seen over development is associated with the development of "top-down" executive processes, but that "bottom-up" regulatory functions will remain impaired irrespective of clinical improvement. If this hypothesis is confirmed, it could have a significant impact on the development of novel treatment interventions. This project is designed to test a model that posits specific mechanisms that are linked to the improvement of ADHD severity over development as distinct from those that cause the disorder. If our hypothesis is confirmed, it could have a significant impact on the development of novel, long-lasting, treatment interventions for this highly impaired group of patients
Keywords: 12 year old; 4 year old; Address; Adult; Affect; Age; Age-Years; alertness; Arousal; Attention deficit hyperactivity disorder; base; Base of the Brain; Behavioral; Behavioral Symptoms; boys; Brain region; Brain Stem; Characteristics; Child; Childhood; Clinical; Cognitive; cognitive control; Comorbidity; Corpus striatum structure; cost; Data Analyses; Data Set; Defect; design; Development; Disease; early childhood; Effectiveness; emerging adult; Environmental Risk Factor; Etiology; executive function; Extroversion; Frequencies (time pattern); functional disability; Functional Magnetic Resonance Imaging; functional outcomes; girls; Goals; Growth; Health; Heart; Heterogeneity; High Prevalence; high risk; Home environment; Impairment; improved; Impulsivity; inattention; Individual; insight; interest; Intervention; introvert; Lead; Link; Literature; Longitudinal Studies; Matched Group; Measures; Mediating; Mental disorders; Modeling; Neurocognitive; Neurocognitive Deficit; neuropsychological; novel; Nursery Schools; Outcome; Parents; Patients; Pattern; Performance; Personality; Positioning Attribute; Prefrontal Cortex; Preschool Child; Process; prognostic indicator; Progress Reports; prospective; Psychopathology; Recruitment Activity; relating to nervous system; Reporting; Research; Risk; Sampling; School-Age Population; Schools; Secondary to; Severities; Sex Characteristics; Short-Term Memory; Staging; Symptoms; System; teacher; Temperament; Testing; theories; Thick; Time; Variant; Work; Youth
Relevance: This project is designed to test a model that posits specific mechanisms that are linked to the improvement of ADHD severity over development as distinct from those that cause the disorder. If our hypothesis is confirmed, it could have a significant impact on the development of novel, long-lasting, treatment interventions for this highly impaired group of patients
Project start date: 2004-02-01
Project end date: 2014-03-31
Budget start date: 1-JUL-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01MH068286-08 (2011): $683572
ADHD: NEURAL CORRELATES OF ADULT OUTCOMES
M Jeffrey
Queens Collegecity: Flushing country: United States (us)
Grant 5R01MH060698-10 from National Institute Of Mental Health
Abstract: This application is based on the hypothesis that at least partially distinct neural and cognitive mechanisms are involved in the etiology of and recovery from Attention-deficit/Hyperactivity Disorder - combined type (ADHD-C). We posit that ADHD-C is due to a primary deficit in a neural system emerging from the reticular formation within the hindbrain/midbrain region that is present early in ontogeny and remains relatively static throughout the lifetime. Further, we posit that the diminution of symptoms frequently seen throughout development is related to the degree to which frontostriatal systems are able to compensate for these early deficits through the use of effort or "top-down" executive control. To test this hypothesis, we propose to use functional magnetic resonance imaging (fMRI) along with neurocognitive measures in three groups of young adults. Two groups consist of patients from a longitudinal sample, all of whom met criteria for ADHD-C during childhood. Among these, many can be clearly identified either as ADHD persisters (ADHD-P) or ADHD remitters (ADHD-R). In addition, we have well-matched controls who never met criteria for any subtype of ADHD. Thus, we will evaluate the neural correlates of diverse developmental pathways in ADHD-C. If our hypotheses are correct, behavioral and fMRI indices of the system emerging the reticular formation should differ from controls in those who had childhood ADHD-C irrespective of adult clinical status. In contrast, measures of frontostriatal function should vary as a function of adult status such that more severe ADHD symptoms in adulthood are associated with poorer efficiency on these measures while those no longer having significant ADHD symptoms should perform more similarly to never-ADHD controls
Keywords: 0-11 years old; 11 year old; 21+ years old; Accounting; Active Follow-up; AD/HD; Address; ADHD; Adolescent; adolescent substance use; Adolescent Youth; Adult; adult human (21+); adult youth; Affect; Area; Arousal; attention deficit hyperactive disorder; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Basal Ganglia; Basal Nuclei; base; Behavioral; Brain; Brain Stem; Brainstem; Causality; Cerebellum; Characteristics; Child; Child Youth; Childhood; children; Children (0-21); Clinical; Cognitive; Comorbidity; Corpus Striatum; Corpus striatum structure; cost; Data; Development; Developmental Process; Diagnosis; disease causation; disease control; disease etiology; Disease remission; disease subtype; disease/disorder etiology; disorder control; disorder etiology; disorder subtype; Dysfunction; eleven year old; Encephalon; Encephalons; Etiology; executive control; executive function; fMRI; follow-up; Functional disorder; Functional Magnetic Resonance Imaging; Generalized Growth; Grant; Growth; Heart; Heterogeneity; Hind Brain; hindbrain; Human, Adult; Human, Child; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Impairment; Impulsivity; inattention; inattentiveness; indexing; Individual; Inferior Frontal Convolution; Inferior frontal gyrus; innervation; innovate; innovation; innovative; Investigators; juvenile; juvenile human; long-term study; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Measures; Mediating; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; meetings; Mesencephalon; Mid-brain; Midbrain; Midbrain structure; Modeling; Motor; MR Imaging; MR Tomography; MRI; MRI, Functional; nerve supply; Nervous; Nervous System, Brain; neural; neural circuit; neural circuitry; Neurocognitive; neuropsychological; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; ontogeny; Outcome; Partial Remission; pathophysiology; pathway; Pathway interactions; Patients; pediatric; Performance; Physiopathology; Position; Positioning Attribute; Probability; proband; Process; programs; Programs (PT); Programs [Publication Type]; Progress Reports; Public Health; public health medicine (field); Recovery; recruit; Recruitment Activity; relating to nervous system; Remission; Reporting; Research; Research Personnel; Researchers; Residual; Residual state; Resolution; response; Reticular Formation; Rhombencephalon; RMSN; Sampling; Severities; striatal; Striate Body; Striatum; Symptoms; System; System, LOINC Axis 4; Technology; Testing; thalamic; Thalamic structure; Thalamus; theories; Time; Tissue Growth; young adult; youngster; youth substance use; Zeugmatography
Project start date: 1999-12-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5R01MH060698-10 (2011): $351656
MODULATION OF LIVER CANCER BY PPARBETA/DELTA
M Jeffrey, Distinguished Professor
Pennsylvania State University-univ Parkcity: University Park country: United States (us)
Grant 5R01CA140369-02 from National Cancer Institute
Abstract: There are more than 14,000 deaths per year due to liver cancer, the most rapidly increasing type of cancer in the United States. In contrast to other cancers, liver cancer frequency and mortality is increasing. There is a distinct need for new approaches to prevent and treat this disease as the current strategies of chemotherapy and surgical treatments are not very effective. Thus, it is essential to delineate new molecular pathways involved in the etiology of liver cancer to provide new strategies with significantly better efficacy to prevent human mortality due to liver cancer. It well established that direct transcriptional up-regulation of target genes by peroxisome proliferator-activated receptor-/ (PPAR/) can modulate cellular homeostasis. However, there is also evidence that PPAR/ has epigenetic activities that include inhibiting expression of proinflammatory cytokines, chemokines and cell adhesion molecules via interacting with other transcription factors. Preliminary data demonstrates that PPAR/ can attenuate liver toxicity and pre-malignant liver tumor formation. Further, ligand activation of PPAR/ can attenuate liver toxicity by down-regulating pro- inflammatory signaling molecules. The central hypothesis of this proposal is that PPAR/ can be specifically targeted to inhibit hepatocarcinogenesis. Aim 1 will test the hypothesis that PPAR/ attenuates tumor promotion during hepatocarcinogenesis. This will be examined by inducing liver cancer using either a chemically-induced model or an HCV-transgenic model using both wild-type and Ppar/-null mice, coupled with treatment with the high affinity PPAR/ ligand GW0742. Aim 2 will test the hypothesis that PPAR/ attenuates tumor promotion by epigenetic modulation of inflammatory signaling in Kupffer cells. This will be examined by analysis of transgenic mice expressing a DNA binding domain mutant form of PPAR/ that can epigenetically interact with other transcription factors, but is incapable of activating PPRE-specific target genes. This analysis will also be coupled with analysis of conditional deletion of PPAR/ in Kupffer cells. Results from these innovative studies will determine if PPAR/ can be an anti-inflammatory molecular target and provide an alternative strategy for preventing and treating liver cancer. Additionally, results from these studies could lead to a significant paradigm shift in treatment strategies for liver cancer and other chronic inflammatory diseases if epigenetic modulation of inflammatory signaling mediated by PPAR/ is shown to effectively prevent hepatocarcinogenesis. The incidence of liver cancer is increasing as compared to other cancers whose incidence has plateaued or is decreasing. Thus, there is a need to develop new strategies to prevent liver cancer. This proposal will examine the etiology of liver cancer with an emphasis on how a nuclear receptor modulates tumor promotion. The goal of this work is to determine if this receptor represents a new target for the prevention and treatment of liver cancer, through either the direct increase in target genes that protect against liver cancer and/or through epigenetic mechanisms that modulate inflammation
Keywords: Affinity; Anti-inflammatory; Anti-Inflammatory Agents; Attenuated; attenuation; cancer type; CCAAT-Enhancer-Binding Proteins; Cell Adhesion Molecules; cell type; Cessation of life; chemokine; chemotherapy; Chronic; Coupled; cytokine; Data; Diethylnitrosamine; Disease; DNA Binding Domain; Epigenetic Process; Etiology; Frequencies (time pattern); Gene Targeting; Goals; Hepatitis C virus; Hepatocarcinogenesis; Hepatotoxicity; Homeostasis; human mortality; Incidence; Inflammation; Inflammatory; inflammatory modulation; innovation; Knockout Mice; Kupffer Cells; Lead; Ligands; Liver; Liver neoplasms; Malignant neoplasm of liver; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Mortality Vital Statistics; mutant; novel strategies; Nuclear Hormone Receptors; Nuclear Receptors; Operative Surgical Procedures; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phase; PPAR-beta; Premalignant; prevent; Prevention; Primary carcinoma of the liver cells; Process; public health relevance; receptor; Role; Signal Transduction; Signaling Molecule; STAT3 gene; Testing; transcription factor; Transgenic Mice; Transgenic Model; treatment strategy; Tumor Promotion; United States; Up-Regulation (Physiology); Work
Project start date: 2010-06-04
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01CA140369-02 (2011): $271930
TRAINING EXECUTIVE, ATTENTION, AND MOTOR SKILLS (TEAMS): PRELIMINARY STUDIES
M Jeffrey
Queens Collegecity: Flushing country: United States (us)
Grant 4R33MH085898-03 from National Institute Of Mental Health
Abstract: The proposed application is to conduct the ground work for the development of "Training Executive, Attention and Motor Skills (TEAMS)," a novel intervention for preschool children with Attention-deficit/Hyperactivity Disorder (ADHD). TEAMS is designed to result in enduring reductions of ADHD symptoms and associated impairments in children, and thus prevent the chronic and highly impairing course that ADHD oftentimes takes throughout the lifespan. TEAMS is based on the notions that 1) the behavioral manifestations of ADHD are the result of deficient neural networks that affect a wide array of neurocognitive and behavioral processes which are not necessarily identical in all children with the disorder; 2) neurodevelopment is sensitive to and can be positively affected by appropriate environmental influences; 3) effective environmental stimulation will be best achieved within a dynamic social context; and 4) the engagement of the child in the core activities of the treatment must be intrinsically rewarding (i.e., fun) rather than extrinsically reinforced (e.g., praise or tokens) in order to facilitate self- imposed continuation of the intervention which will lead to generalization over time and across settings. We propose that these goals can be achieved through the use of game-like activities which place demands on an array of neurocognitive and motor skills, interspersed with periods of physical exercise. TEAMS will be administered within the context of a small group setting (Approximately 5 children). A concurrently-occurring parent group will focus on helping them to engage their children in these game-like and exercise activities at home. In addition, parents will be asked to encourage such play among their child and his/her peers so as to facilitate implementation outside of our clinical setting
Keywords: active method; Adolescence; Adult; Affect; Aftercare; Animals; Attention; Attention deficit hyperactivity disorder; base; Behavior; Behavioral; Biological Neural Networks; blind; Brain; brief intervention; Categories; Child; Chronic; Clinical; Clinical assessments; Clinical Trials; Cognitive; Computer Programs and Programming; computerized; cost; Data; data acquisition; Data Analyses; Dendritic Spines; design; Development; Diamond; Disease; Double-Blind Method; Educational aspects; effective therapy; efficacy testing; Equilibrium; Evaluation; Exclusion Criteria; executive function; Exercise; falls; Family; Frequencies (time pattern); functional disability; Functional Magnetic Resonance Imaging; Goals; Growth; Home environment; Human; Impairment; improved; inclusion criteria; Individual; Intervention; Lead; Literature; Longevity; Manuals; Measures; meetings; Methodology; Monitor; motor control; Motor Skills; Names; Nature; Neocortex; neural circuit; Neurocognitive; Neurocognitive Deficit; neurodevelopment; Neurodevelopmental Disorder; neuroimaging; neurotransmission; novel; Nursery Schools; Outcome; Parents; Participant; Pattern Recognition; peer; Performance; Phase; Play; Preparation; Preschool Child; prevent; Procedures; Process; Production; programs; Protocols documentation; Randomized Clinical Trials; relating to nervous system; Relative (related person); Reporting; Research; research clinical testing; Research Personnel; response; Rewards; Sampling; satisfaction; scaffold; Schools; Series; Short-Term Memory; skills; social; Social Environment; Social Interaction; Societies; Specific qualifier value; Stress; success; Symptoms; teacher; Testing; Therapeutic; Time; TimeLine; Training; Translating; treatment duration; trial comparing; Work
Relevance: This project is designed to develop a novel intervention for preschool children with Attention- deficit/Hyperactivity Disorder (ADHD) that will result in enduring reductions of ADHD symptoms and associated impairments in children, and thus prevent the chronic and highly impairing course that ADHD oftentimes takes throughout the lifespan
Project start date: 2009-04-10
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-MH-09-021
4R33MH085898-03 (2011): $207722
MECHANISMS OF MINDFULNESS: EFFECTS ON SLEEP QUALITY, STRESS PHYSIOLOGY & CVD RISK
M Jeffrey, Licensed Clinical Psychologist
Duke Universitycity: Durham country: United States (us)
Grant 5R00AT004945-04 from National Center For Complementary & Alternative Medicine
Abstract: The goal of this K99/R00 application is to understand how mindfulness training may impact biobehavioral factors implicated in increased risk of cardiovascular disease (CVD). These factors include sleep (quality and quantity), psychological distress, and stress reactivity, including markers of inflammation. The candidate´s training plan includes focused, mentored training in the areas of (a) sleep and its relation to CVD risk and pathophysiological mechanisms; (b) clinical trials methodology; and (c) structural linear modeling to guide translation of experimental data into novel interventions for CVD risk reduction. The K99 research project proposes to model individual differences in mindfulness-based stress reduction (MBSR) treatment outcomes, with a focus on examining intervention-related changes in mindfulness as a predictor of self-reported changes in cognitive and emotional functioning and sleep quality and duration. In addition, the K99 phase includes mentorship in statistical modeling of mechanisms linking psychological distress, sleep disturbance, inflammation and increased CVD risk. The R00 research project proposes a study of 50 men and women to test the hypothesis that MBSR-related increases in mindfulness predict improvements in sleep quality and quantity and decreases in physiological responses to an acute laboratory stressor, including inflammation. It is further hypothesized that improvements in sleep quality and quantity and attenuated stress physiology will be mediated, in part, by adaptive changes in cognitive and emotional processes, including less perseveration and increased emotion regulation. Finally, we hypothesize a bidirectional relationship between improved sleep and attenuated stress physiology following MBSR training. Modeling analyses will be translated into the development of an innovative brief intervention aimed at reducing biobehavioral risk for CVD by improving sleep quality, ameliorating psychological distress, and attenuating stress reactivity. This translational research program will extend existing knowledge by innovatively integrating work in psychology, complementary and alternative medicine (CAM), sleep, psychophysiology, immunology and CVD. This award will establish the candidate´s career in the study of mindfulness as a mechanism of mind-body health and CVD risk reduction. This project aims to reduce CVD risk by informing novel treatment approaches to poor sleep quality and excessive stress reactivity, two factors associated with increased risk of CVD
Keywords: Acute; acute stress; Adult; Affect; Anger; Anxiety; Area; Arousal; Attention; Attenuated; Award; base; Behavioral; Behavioral Medicine; Behavioral Sciences; Binge Eating; Binge eating disorder; biobehavior; Biological; biomarker; Blood Glucose; Blood Pressure; body-mind; brief intervention; Cardiovascular Diseases; cardiovascular disorder risk; Cardiovascular system; career; career development; Catecholamines; Chronic; Clinical; Clinical Investigator; Clinical Research; Clinical Skills; Clinical Trials; Cognitive; Complementary and alternative medicine; Complex; Control Groups; Coupled; Data; Development; Disease; Distress; Doctor of Philosophy; Effectiveness; emotion regulation; Emotional; Emotional Stress; Ensure; Equation; Funding; glucose metabolism; Goals; Health; Health behavior; Heart Rate; Home environment; Hostility; Hydrocortisone; Immune; immune activation; Immunology; improved; indexing; Individual; Individual Differences; Inflammation; Inflammatory; inflammatory marker; Inflammatory Response; innovation; insight; Institution; Insulin Resistance; Integrative Medicine; Interleukin-6; Intervention; Interview; Knowledge; Laboratories; Lead; Leukocytosis; Linear Models; Link; Measures; Mediating; Medical; men; Mental Depression; Mentors; Mentorship; Metabolic; Methodology; Mind-Body Intervention; Mind-Body Relationship (Physiology); mindfulness; mindfulness-based stress reduction; Modeling; Neurosecretory Systems; NIH Program Announcements; Non-Insulin-Dependent Diabetes Mellitus; novel; Obesity; Outcome; Pathway interactions; Patient Self-Report; Patients; Phase; Physiological; Physiology; preempt; Principal Investigator; Process; Productivity; programs; Psychiatry; psychologic; psychological distress; Psychological Impact; Psychologist; Psychology; Psychophysiology; psychosocial; public health medicine (field); public health relevance; Regulation; Relative (related person); Research; Research Personnel; Research Project Grants; Resources; response; restoration; Risk; Risk Factors; Risk Reduction; Self Care; Sleep; Sleep Disorders; Sleep disturbances; Statistical Models; statistics; Stress; stressor; System; Testing; theories; Training; Translating; Translational Research; Translations; Treatment outcome; Universities; Woman; Work
Project start date: 2008-09-30
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-297
5R00AT004945-04 (2011): $240349
GENERALIZED CAUSAL MEDIATION ANALYSIS FOR SOCIAL ENVIRONMENT AND HEALTH RESEARCH
M Jeffrey, Assistant Professor
Case Western Reserve Universitycity: Cleveland country: United States (us)
Grant 1R01DE022674-01 from Office Of The Director, National Institutes Of Health
Abstract: The effects of the social environment on health outcomes have been demonstrated in numerous research studies. However, the mechanisms or intermediate variables through which these effects occur are largely unknown. While methods for mediation analysis exist for the study of intermediate variables (or mediators), these methods are inadequate for handling the challenging features of social environment data. The proposed research will develop new mediation analysis methods using a potential outcomes and structural (causal) model framework. Our two-pronged approach, referred to as generalized causal mediation analysis, will provide new methods for both the fitting of causal models and the computation of mediation effects. In particular, we will extend previous methods by handling models with the following features 1) mixed discrete and continuous variables, 2) multiple exposure variables, 3) heterogeneous mediation effects, 4) multi-level data, and 5) latent variables. Further extending the causal model framework, in which mediation has an intervention interpretation, we will develop a method to predicting the effect of a new intervention. This approach will involve user augmentation of a fitted causal model, thus synthesizing theory and empirical results. The methods will be applied to three motivating datasets 1) family environment and dental caries data from 224 very low birth weight and normal birth weight adolescents and their parents; 2) data from a study of an intervention to prevent STDs involving 1357 suburban high schools students; and 3) data from a study of oncologist-patient communication and its effect on patient decision satisfaction. The new methods will be evaluated and refined through the data applications and through simulation studies. Finally, the project will develop user-friendly computer programs to allow behavioral and other health researches to apply the new methods. The new methods will allow a more refined, valid, and thorough exploration of mediating pathways for social environment effects. They will also facilitate the formulation of effective behavioral and other interventions, utilizing knowledge about social environment mechanisms, to improve health outcomes. This project will develop new statistical methods that will help researchers explain the relationship between social environments and health outcomes. The new methods, designed to model complex causal relationships, will be applied to data from dental caries, school STD prevention, and oncologist- patient communication studies. The improved understanding provided by the new methods will facilitate the design of effective new behavioral and other interventions for preventing and reducing the many diseases on which the social environment has an impact
Keywords: Address; Adolescent; Algorithms; base; Behavior Therapy; Behavioral; Birth Weight; cancer prevention; Communication; Complex; Computer Programs and Programming; Computing Methodologies; Data; Data Analyses; data modeling; Data Set; Dental caries; design; Disease; Drug Formulations; Environment; Evaluation; Family; Funding Opportunities; Health; health disparity; Heterogeneity; high school; improved; Individual; interest; Intermediate Variables; Intervention; intervention effect; Intervention Studies; Investigation; Knowledge; Link; Measurement; Mediating; Mediation; Mediator of activation protein; Methodology; Methods; Mission; Modeling; Monte Carlo Method; novel; Oncologist; Outcome; Parents; Pathway interactions; Patients; prevent; Prevention; Research; Research Personnel; research study; response; satisfaction; Schools; simulation; Social Environment; Statistical Methods; Structural Models; Students; suburb; Techniques; Testing; theories; user friendly software; user-friendly; Variant; Very Low Birth Weight Infant
Relevance: This project will develop new statistical methods that will help researchers explain the relationship between social environments and health outcomes. The new methods, designed to model complex causal relationships, will be applied to data from dental caries, school STD prevention, and oncologist- patient communication studies. The improved understanding provided by the new methods will facilitate the design of effective new behavioral and other interventions for preventing and reducing the many diseases on which the social environment has an impact
Project start date: 2011-09-23
Project end date: 2016-08-31
Budget start date: 23-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-DA-11-003
1R01DE022674-01 (2011): $212960
A VITAL TOOL FOR THE STUDY OF DBA:THE DIAMOND BLACKFAN ANEMIA REGISTRY
M Jeffrey, Principal Investigator
Feinstein Institute For Medical Researchcity: Manhasset country: United States (us)
Grant 5R01HL079571-07 from National Heart, Lung, And Blood Institute
Abstract: The Diamond Blackfan Anemia Registry (DBAR) is a comprehensive database of patients with the rare inherited bone marrow failure syndrome Diamond Blackfan anemia (DBA). DBA is a heterogeneous genetic disorder characterized by pure red cell aplasia, congenital anomalies and a predisposition to cancer. Anemia usually presents in infancy or early childhood and approximately 50% of patients have at least one congenital anomaly. The actuarial cancer risk although increased, is as of yet, undetermined. To date six genes encoding ribosomal proteins, of both the small and large subunits, have been found to be mutated, representing nearly 50% of patients with DBA. Of note, "affected" individuals within the same family may vary dramatically as to the degree of anemia, response to corticosteroids, the presence of congenital anomalies and the development of cancer. Prior to the development of the DBAR our knowledge regarding the epidemiology and response to various treatment modalities was determined exclusively from literature reports. The DBAR has been developed in order to provide a well-characterized patient substrate linked to biological samples, permitting the study of the epidemiology and biology of DBA. The objective of this application is to improve and exploit the DBAR in order to 1) facilitate investigations into the epidemiology and biology of DBA; 2) provide an accurate phenotype of DBA patients to facilitate genotype-phenotype correlations; 3) provide access of well characterized patients to treatment protocols; 4) provide patients and their health care providers access to research studies; 5) provide patients and their health care providers with results of research studies; 6) serve as a resource to patients and their doctors to guide diagnostic, therapeutic, and reproductive decisions; 7) develop an accurate and rapid diagnostic screening test for DBA; and 8) encourage national and international collaborative research. By exploiting a well-characterized patient population, the Diamond Blackfan Anemia Registry, the molecular basis of red blood cell production and its link to ribosome assembly and function and cancer predisposition, can be explored. The goal of this project is to utilize this database for detailed analysis of the degree of anemia, treatment response, and presence of congenital anomalies and development of cancer in DBA patients. This will lead to insights into the etiology of birth defects and cancer in these patients and in the population at large and ultimately lead to improved clinical care for DBA patients
Keywords: Adrenal Cortex Hormones; Affect; Anemia; Apoptotic; base; Biological; Biology; Birth Defects; blood corpuscles; Blood erythrocyte; Blood normocyte; Bone marrow failure; Canada; cancer risk; Cancers; Causality; Cell Function; Cell physiology; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Clinical; clinical care; clinical data repository; clinical data warehouse; Clinical Research; Clinical Study; Complex; Conduct Clinical Trials; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Malformation; Corticoids; Corticosteroids; Data Banks; Data Bases; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; Defect; demographics; Development; Diagnosis; Diagnostic; Diamond-Blackfan anemia; Disease; disease causation; disease etiology; Disease remission; disease/disorder; disease/disorder etiology; Disorder; disorder etiology; Dysmyelopoietic Syndromes; early childhood; Epidemiology; epidemiology study; Erythrocyte Aplasia; Erythrocytes; Erythrocytic; Erythroid; Etiology; Event; experiment; experimental research; experimental study; Family; Forecast of outcome; gene discovery; gene product; Genes; Genetic Alteration; Genetic Change; Genetic Condition; Genetic defect; Genetic Diseases; genetic disorder; genetic pedigree; genome mutation; Genotype; Goals; health care personnel; Health Care Professional; Health Care Providers; health care worker; Health Personnel; Health profession; Health Professional; health provider; healthcare personnel; Healthcare professional; Healthcare Providers; Healthcare worker; heavy metal lead; heavy metal Pb; Hematologic Cancer; Hematologic Malignancies; Hematologic Neoplasms; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematologist; Hematopoiesis; Hematopoietic Cancer; Hematopoietic Cellular Control Mechanisms; Hereditary; Hereditary Disease; hereditary disorder; improved; Incidence; Individual; infancy; infantile; Inherited; insight; interest; International; Investigation; Knowledge; Laboratories; Laboratory Research; Laboratory Study; Lead; Link; Literature; malignancy; Malignant Hematologic Neoplasm; Malignant Neoplasms; Malignant Tumor; Marrow erythrocyte; medical personnel; Modality; Molecular; Molecular Disease; Molecular Genetic Abnormality; Mutate; Mutation; myelodysplasia; Myelodysplastic Syndromes; neoplasm/cancer; Outcome; outcome forecast; Pancytopenia; patient population; Patients; Pb element; Pedigree; pedigree structure; Penetrance; Phenotype; Population; Predisposition; Production; Prognosis; Proteins; Protocols, Treatment; public health relevance; Publishing; Pure Red-Cell Aplasia; Rare Diseases; Rare Disorder; Red Blood Cells; Red blood corpuscule; Red Cell; Red cell of marrow; Red-Cell Aplasia, Pure; Regimen; Registries; relational database; Remission; Reporting; reproductive; Research; Research Resources; research study; Resources; response; Reticuloendothelial System, Erythrocytes; RGM; Ribosomal Proteins; Ribosomes; RMSN; Sampling; screening; Screening procedure; screenings; Smoldering Leukemia; Subcellular Process; Susceptibility; Syndrome; Testing; Therapeutic; Therapeutic Corticosteroid; Therapeutic Human Experimentation; Therapeutic Research; Time; tool; Treatment Protocols; treatment provider; Treatment Regimen; treatment response; Treatment Schedule; United States
Relevance: Relevance By exploiting a well-characterized patient population, the Diamond Blackfan Anemia Registry, the molecular basis of red blood cell production and its link to ribosome assembly and function and cancer predisposition, can be explored. The goal of this project is to utilize this database for detailed analysis of the degree of anemia, treatment response, presence of congenital anomalies and development of cancer in DBA patients. This will lead to insights into the etiology of birth defects and cancer in these patients and in the population at large and ultimately lead to improved clinical care for DBA patients
Project start date: 2004-09-30
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01HL079571-07 (2011): $415000
CELL BIOLOGY OF ENTEROVIRUS INFECTION IN POLARIZED EPITHELIAL CELLS
M Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Grant 1R56AI072490-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Summary Enteroviruses are transmitted by the fecal-oral route, and must cross the intestinal mucosa to initiate infection. The intestines are lined by polarized epithelial cells, with distinct apical and basolateral surfaces; intercellular tight junctions prevent virus access to receptors on basolateral membranes. Many enteroviruses, including many coxsackie B viruses (CBV) and echoviruses (EV), appear to have evolved independently to bind to decay accelerating factor (DAF), a molecule expressed on the surface of polarized epithelium. We believe that these viruses use DAF to interact with epithelial cells in the intestinal lumen DAF does more than simply provide a site for virus attachment. We recently found that it initiates at least two intracellular signaling pathways required for CBV entry and infection in polarized cells activation of Abl kinase leads to actin rearangements and virus movement to the tight junction, where interaction with the coxsackievirus and adenovirus receptor (CAR) initiates the uncoating process that releases viral RNA; activation of Fyn kinase triggers virus internalization in caveolae, and delivery to the endoplasmic reticulum (ER) where uncoating is completed before replication ensues. These results suggest that infection of polarized cells is likely to involve distinctive cell biological mechanisms. We propose three sets of experiments to examine the cell biology of infection in polarized epithelium. 1. We will define the pathway by which DAF-binding EV enter polarized epithelium, following the entry of labeled virus, and using specific inhibitors (drugs, siRNAs) to dissect the underlying cellular processes. 2. We will determine the function of actin rearrangements and changes in microvillus architecture during virus entry, and identify the mechanism by which actin reorganization is initiated in response to virus- DAF interaction. 3. We will screen an siRNA library to identify signaling molecules required for CBV entry into polarized epithelium, and define the role of specific signaling molecules in the process of infection. Relevance Enteroviruses are the major cause of viral meningitis, and the second major cause of myocarditis in the US, and interaction with polarized epithelium is the first step in infection. Understanding the special mechanisms by which they infect polarized cells will reveal new potential drug targets
Keywords: Actins; adenovirus receptor; Apical; Architecture; basolateral membrane; Binding (Molecular Function); Biological; Capsid; Caveolae; CD55 Antigens; Cell membrane; Cell physiology; Cells; Cellular biology; cellular microvillus; Coxsackie B Viruses; Coxsackie Viruses; Cytoskeleton; Data; Depth; DNA Sequence Rearrangement; Drug Delivery Systems; Echo Viruses; Echovirus Infections; Endoplasmic Reticulum; Enterovirus; Enterovirus Infections; Epithelial Cells; Epithelium; Event; gastrointestinal microvillus; Guanosine Triphosphate Phosphohydrolases; Human; Human Echovirus 6; Infection; inhibitor/antagonist; Intervention; intestinal epithelium; Intestinal Mucosa; Intestines; Label; Libraries; Movement; Myocarditis; Numbers; Oral; pathogen; Pathway interactions; Penetration; Pharmaceutical Preparations; Phosphotransferases; polarized cell; prevent; Process; receptor; research study; response; Role; Route; Signal Pathway; Signal Transduction; Signaling Molecule; Simian B disease; Site; Small Interfering RNA; Surface; Tight Junctions; Viral meningitis; viral RNA; Virus
Project start date: 2007-09-15
Project end date: 2008-06-30
Budget start date: 15-SEP-2007
Budget end date: 30-JUN-2008
1R56AI072490-01A1 (2007): $404692
Sponsored Links Excellgen http://Excellgen.com
MUTAGENESIS OF P53 BY REACTIVE PAH AND ROS
M Jeffrey, Professor
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01ES015662-04 from National Institute Of Environmental Health Sciences
Abstract: Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental air pollutants that result from fossil fuel combustion and cigarette smoking. PAH exposure is a major risk factor in human lung carcinogenesis. A critical step in multi-stage carcinogenesis is the mutagenic event that results from the formation of DNA adducts. There are three principle routes of metabolic activation of PAH resulting in the formation of diol- epoxides, radical cations, or reactive and redox-active o-quis. Each of these reactive metabolites have the potential to form DNA-adducts and these adducts may lead to mutation. We are using two approaches to model PAH carcinogenesis, a highly versatile yeast system and human lung cell lines. In lung cancer, the gene most often mutated is p53 where three distinguishing characteristics are found in lung cancer. (1) The pattern of mutations is dominated by G to T transversions; (2) The spectrum of mutations reveals hotspot codons, a few of which are unique to lung cancer; (3) The pattern and spectrum of mutations show a strand bias for mutations on the non-transcribed strand. Our systems use genetic selection methods so that change-in- function mutations can be detected with ease. The yeast reporter system for p53 relies on wild-type p53 binding to a promoter to drive an adenine reporter causing mutant colonies turn red. Our preliminary data suggest that PAH o-quis, when permitted to undergo redox-cycling, generate 8-oxo-dGuo to cause predominantly G to T transversions with a modest, but significant, preference for hotspots but with no strand bias. We recently devised a system to detect mutations in human lung cells using a p53 dependent promoter to direct transcription of the Herpes TK gene. In this system p53+ cells are killed by exposure to ganciclovir while p53 cells are resistant. The mutant p53 is next rescued from the cells using the yeast system and then sequenced. Using these assays to model p53 mutagenesis we will (1) Determine the role of repair genes on p53 mutagenesis and compare different PAH metabolites, (2) Map the locations of PAH induced DNA lesions in the p53 gene(3) determine if PAH-metabolites can mutate p53 in lung cells. Our hypothesis is that PAH o- quis and the ROS they generate provide a route to the p53 mutations found in lung cancer. Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental air pollutants that result from fossil fuel combustion and cigarette smoking. PAH exposure is a major risk factor in human lung carcinogenesis. This proposal will study the mutagenesis of the p53 oncogene by PAH and their metabolites
Keywords: 8-Oxo-2`-Deoxyguanosine; A549; adduct; Adenine; Aromatic Polycyclic Hydrocarbons; base; Binding (Molecular Function); Biological Assay; carcinogenesis; Carcinogens; Cations; Cell Culture Techniques; cell killing; Cell Line; Cells; Characteristics; cigarette smoking; Code; Codon Nucleotides; Color; Data; design; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA lesion; Environmental Air Pollutants; Environmental Pollutants; Epithelial Cells; Epoxy Compounds; Event; Exposure to; Fossil Fuels; Frequencies (time pattern); Ganciclovir; gene repair; Genetic Transcription; Glycols; Health; HSV-Tk Gene; Human; In Situ; In Vitro; Inherited; Knock-out; Lead; Lesion; Ligation; Location; Lung; Lung Adenocarcinoma; lung carcinogenesis; Malignant neoplasm of lung; Mammalian Cell; Maps; Mediating; Metabolic Activation; Metabolic Pathway; Methods; Modeling; Mutagenesis; Mutagens; mutant; Mutate; Mutation; Mutation Spectra; novel; OGG1 gene; Oncogenes; Oxidation-Reduction; Pathway interactions; Pattern; Pharmaceutical Preparations; preference; Promotor (Genetics); Protein p53; Quis; Reactive Oxygen Species; Relative (related person); repaired; Reporter; Reporter Genes; research study; Resistance; Risk Factors; Role; Route; Selection (Genetics); Site; Staging; System; Techniques; Testing; TK Gene; Tobacco; TP53 gene; Transcription-Coupled Repair; Transcriptional Activation; Yeasts
Project start date: 2008-04-08
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01ES015662-04 (2011): $279344
5R01ES015662-03 (2010): $310381
MODULATION OF SKIN CANCER BY PPARBETA/DELTA
M Jeffrey, Distinguished Professor
Pennsylvania State University-univ Parkcity: University Park country: United States (us)
Grant 5R01CA124533-05 from National Cancer Institute
Abstract: Peroxisome proliferator-activated receptor-B/d (PPARB/d)-null mice exhibit enhanced tumor formation in both skin and colon and ligand activation of PPARB/d inhibits tumor multiplicity in both skin and colon. The mechanisms underlying the inhibition of tumorigenicity by a PPARB/d ligand is likely due to the induction of terminal differentiation and increased apoptosis that requires PPARB/d since these effects are not found in similarly treated PPARB/d-null mice. Additionally, PPARB/d-dependent modulation of ubiquitin-mediated regulation of critical cell proliferation/apoptotic pathways could also be a central mechanism underlying the inhibition of tumorigenicity by PPARB/d ligands. The central hypothesis of this proposal is that the PPARB/d modulates the molecular events that lead to skin carcinogenesis from genetic and chemical factors. Inhibition of skin carcinogenesis by cyclooxygenase (COX) inhibitors is 1 approach that is known to inhibit skin tumorigenicity, but is not 100% effective. We have recently demonstrated that inhibition of chemically-induced skin cancer by COX inhibition is independent of PPARB/d. Additionally, others have recently shown that inhibition of cell proliferation by ligand activation of PPARB/d can be greatly enhanced when coupled with inhibition of COX. The first specific aim is to test the hypothesis that combining ligand activation of PPARB/d with inhibition of COX activity will inhibit skin carcinogenesis with greater efficacy than either treatment by itself. This will be examined by 2-stage chemical carcinogen testing in wild-type and PPARB-null mice, in the presence or absence of COX inhibitors and/or a specific PPARB/d ligand. The inhibitory action of this combined approach will be examined during tumor initiation and progression, and in mice with pre-existing tumors. The second specific aim will test the hypothesis that PPAR?/d-dependent up-regulation of ubiquitin C expression will attenuate skin carcinogenesis. Analysis of keratinocyte-specific ubiquitin C transgenic will determine if PPARB/d-dependent modulation of ubiquitin expression can ameliorate the enhanced tumorigenicity observed in the absence of PPARB/d-dependent ubiquitin C expression, and identify critical PPARB/d-mediated, ubiquitin-dependent pathways that lead to skin cancer. Collectively, these studies will determine if combining ligand activation of PPARB/d with COX inhibition has greater efficacy at inhibiting tumor growth and/or tumor multiplicity than either single treatment and elucidate the mechanisms of PPARB/d-mediated inhibition of chemically-induced skin carcinogenesis. Results from these studies will provide useful novel targets for chemoprevention or chemotherapy that will likely lead to translational research in humans. Lay relevance More than 1 million cases of skin cancer are diagnosed annually within the United States. The annual cost of all cancers exceeds billions of dollars. Risk factors for skin cancer include UV light and exposure to environmental chemical carcinogens. Results from these studies will determine if a combinational approach can more effectively inhibit skin cancer, determine the critical stage of skin carcinogenesis where PPARB-dependent regulation is significant, and provide new molecular targets to inhibit/prevent chemically-induced skin cancer
Keywords: (5Z, 8Z, 11Z, 14Z)-Icosa-5, 8, 11, 14-tetraenoate, hydrogen-donor[{..}]oxygen oxidoreductase; Actinic Rays; APF-1; Apoptosis; Apoptosis Pathway; Apoptotic; Arachidonic Acid Cyclooxygenase; ATP-Dependent Proteolysis Factor 1; Attenuated; biological signal transduction; cancer diagnosis; Cancer Induction; cancer progression; Cancers; Carcinogen Tests; carcinogenesis; Carcinogenesis Tests; Carcinogenic Activity Tests; Carcinogenic Potency Tests; Carcinogenicity Tests; Cell Communication and Signaling; Cell Death, Programmed; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; Cellular Proliferation; chemical carcinogen; chemical genetics; Chemicals; Chemoprevention; chemotherapy; Colon; cost; Coupled; COX; COX inhibitor; Cyclo-Oxygenase; Cyclooxygenase; Cyclooxygenase Inhibitors; Data; environmental chemical; Event; Exhibits; Exposure to; Exposure to ultraviolet radiation; Fatty Acid Cyclo-Oxygenase; heavy metal lead; heavy metal Pb; High Mobility Protein 20; HMG-20; Human; Human, General; Hydroperoxide Cyclase; Inhibition of Cell Proliferation; Inhibitors, Cyclo-Oxygenase; Intracellular Communication and Signaling; keratinocyte; keratinocyte differentiation; Knockout Mice; Laboratories; Lead; Ligands; malignancy; Malignant Neoplasms; Malignant Skin Neoplasm; Malignant Tumor; Malignant Tumor of the Skin; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Melanoma and Non-Melanoma Skin Cancer; Mice; Mice, Knock-out; Mice, Knockout; Molecular; Molecular Target; Murine; Mus; Negative Control of Cell Proliferation; Negative Regulation of Cell Proliferation; neoplasm progression; neoplasm/cancer; neoplastic progression; novel; Null Mouse; pathway; Pathway interactions; Pb element; Peroxisome Proliferator-Activated Receptors; PGH Synthase; PGH2 Synthetase; Polyubiquitin Gene Product; PPAR; prevent; preventing; Prostaglandin Cyclo-Oxygenase; Prostaglandin Cyclooxygenase; Prostaglandin Endoperoxide Synthase Inhibitors; Prostaglandin Endoperoxide Synthetase; Prostaglandin G-H Synthase; Prostaglandin H Synthase; Prostaglandin H2 Synthetase; Prostaglandin Synthase; Prostaglandin Synthase Inhibitors; Prostaglandin Synthesis Antagonists; Prostaglandin Synthetase; Prostaglandin-Endoperoxide Synthase; Regulation; Risk Factors; Role; Signal Transduction; Signal Transduction Systems; Signaling; Skin; Skin Cancer; Skin Cancer, Including Melanoma; Skin Carcinogenesis; social role; Staging; Sun/Ultra-Violet Rays; Testing; transgenic; Transgenic Organisms; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; tumor; tumor growth; tumor initiation; tumor progression; Tumorigenicity; Tumorigenicity Tests; Ubiquitin; Ubiquitin C; ultraviolet light; ultraviolet radiation; Ultraviolet Radiation Related Exposure; Ultraviolet Rays; United States; Up-Regulation; Up-Regulation (Physiology); Upregulation; UV exposure; UV radiation; UV Radiation Exposure; Wild Type Mouse
Project start date: 2007-03-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5R01CA124533-05 (2011): $215657
NOVEL MECHANISMS UNDERLYING DEPRESSION: PET IMAGING OF THE KAPPA OPIOID RECEPTOR
M Jeffrey, Research Scientist
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R21MH091553-01A1 from National Institute Of Mental Health
Abstract: Our understanding of the pathophysiology underlying major depressive disorder (MDD) is incomplete. A great deal of research has focused on the role of disruptions in monoamine neurotransmitter systems in the etiology of MDD (Leonard 2000), and all existing classes of FDA-approved antidepressant medication act on these systems (Lopez-Munoz and Alamo 2009). However, only a minority of patients with MDD achieve remission after well-administered therapeutic trials of existing antidepressant medications (Trivedi et al 2006). Novel studies investigating other molecular pathways that may be involved in the pathophysiology of MDD are needed, and may in turn suggest opportunities for the development of new antidepressant treatments. Both early life and recent life stress are potent risk factors for the development of MDD in adulthood. The kappa opioid receptor (KOR) is stimulated by the endogenous kappa opioids, dynorphins, in response to stress. Evidence from a large, consistent animal literature, and from several studies in humans, suggests that KOR stimulation may contribute to the pathophysiology of MDD, and that KOR may therefore represent a novel molecular target for the development of antidepressant medications. KOR is stimulated by dynorphins in response to stress; KOR agonists exacerbate several animal models of depression, and KOR antagonists have antidepressant effects in these models. In humans, KOR agonists lead to dysphoria in normal controls, and have therapeutically mood-lowering (anti-manic) properties in one study in bipolar disorder. KOR stimulation may exert effects on mood through modulating dopamine release in the nucleus accumbens, a brain region central to processing reward which is implicated in the pathophysiology of depression, and through modulatory effects on serotonin release. The primary aim of this study is to compare regional brain KOR binding potential (BPF, proportional to the total number of available receptors) between subjects with MDD and healthy controls in vivo using positron emission tomography (PET), which has not been assessed to date. This will be done using a KOR-specific PET tracer validated in our institution and characterized further in a human test-retest reliability study, [11C]GR103545. Lower KOR BPF in subjects with MDD compared to controls is hypothesized in two regions implicated in the pathophysiology of MDD in which KOR activation occurs in response to stress ventral striatum and hippocampus. This hypothesis is based on activation of KOR in animal models of depression, which leads to compensatory KOR downregulation. In an exploratory manner, the relationship between life stress and KOR binding will be examined, to translate this finding from rodents into humans. Both early life abuse/neglect and recent stressful life events will be examined as predictors of KOR binding. This study may identify a biological pathway through which environmental adversity contributes to the development of MDD, and may provide a rationale for further development of a novel class of antidepressant, the KOR antagonists. Approximately 33 million adults in the United States (15% of the U.S. population) have suffered from major depressive disorder during their lifetime, and approximately 13 million Americans have experienced MDD in the past year (Kessler et al 2003). Existing treatments for depression are effective in only a minority of patients. Increasing our understanding of the role of the kappa opioid system in the pathophysiology of depression would provide the rationale for further development of a new class of antidepressant medication that could potentially reduce the very large morbidity and mortality caused by MDD
Keywords: abuse neglect; Adult; Agonist; American; Animal Model; Animals; Antidepressive Agents; base; Binding (Molecular Function); Biological; Bipolar Disorder; Brain; Brain region; Data; Development; Disease remission; disorder control; Dopamine; dorsal raphe nucleus; Down-Regulation; Dynorphins; dysphoria; Early-life trauma; Etiology; Event; experience; FDA approved; Functional disorder; Hippocampus (Brain); Human; Image; in vivo; Institution; Interview; Lead; Life; Life Stress; Literature; Major Depressive Disorder; Manic; Mental Depression; Minority; Modeling; Molecular; Molecular Target; monoamine; Moods; Morbidity - disease rate; Mortality Vital Statistics; neglect; Neurotransmitters; norbinaltorphimine; novel; Nucleus Accumbens; Opioid; Opioid Receptor Binding; Pathway interactions; Patients; Pattern; pediatric trauma; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Property; putamen; Questionnaires; receptor; Receptor Activation; receptor downregulation; Receptors, Opioid, kappa; Research; response; reward processing; Risk Factors; Rodent; Role; salvinorin A; Serotonin; single episode major depressive disorder; Stress; System; Testing; Therapy Clinical Trials; Tracer; Translating; United States; Ventral Striatum
Relevance: Approximately 33 million adults in the United States (15% of the U.S. population) have suffered from major depressive disorder during their lifetime, and approximately 13 million Americans have experienced MDD in the past year (Kessler et al 2003). Existing treatments for depression are effective in only a minority of patients. Increasing our understanding of the role of the kappa opioid system in the pathophysiology of depression would provide the rationale for further development of a new class of antidepressant medication that could potentially reduce the very large morbidity and mortality caused by MDD
Project start date: 2011-08-16
Project end date: 2013-07-31
Budget start date: 16-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-069
1R21MH091553-01A1 (2011): $219186
ENCODING AND REMEMBERING EVENTS ACROSS THE LIFE SPAN
M Jeffrey, Associate Professor
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R01AG031150-04 from National Institute On Aging
Abstract: Older adults arrive in the neurological clinic with a variety of complaints about their changing cognitive profile. These include reduced interest in hobbies and activities, repeating stories and statements, trouble learning how to use new tools and appliances, difficulty keeping track of what day it is, and difficulty remembering appointments. Such complaints have a striking feature in common They all appear to be related to one´s mental representation of "what is happening now." Recent research in cognitive psychology and neuroscience has begun to explain how people construct such representations and update them to facilitate perception and memory. This research suggests that the segmentation of ongoing activity into meaningful events is crucial to later memory for those events. However, little is known about how these mechanisms change with aging and dementia. The specific aims of this research address this lacuna Specific Aim 1 Identify cognitive mechanisms of effective event segmentation. What distinguishes those individuals who segment events effectively from those who do not? Does this change across the lifespan? The proposed research will address these questions using psychometric and functional and structural neuroimaging methods. Specific Aim 2 Assess the contribution of effective event segmentation to memory in older adults. In younger adults event segmentation is associated with updating the current contents of short-term memory and with long-term memory retention. The proposed research will investigate how the relations between event segmentation, online memory updating and long-term memory change with age using behavioral and neuroimaging methods. Specific Aim 3 Test interventions to facilitate effective encoding of events. To the extent that effective event segmentation helps memory, improving event segmentation may improve memory. The proposed research will test interventions intended to improve memory by facilitating effective event segmentation. This research proposed here is all based on tasks in which observers comprehend and remember movies and stories that are closer to real-life activity than typical laboratory materials. The tasks are not too different from everyday comprehension of ongoing activities and conversations. These features improve the chances that this approach to event perception and memory may generalize to the memory complaints common to older adults. Declines in memory for everyday events are one of the common complaints of aging. Recent research with younger adults suggests that "chunking" ongoing activity into meaningful events is important for later memory. The proposed research investigates how the mind and brain do this chunking, how it changes as people age, and what interventions might improve its effectiveness
Keywords: Accounting; Address; Age; age related; Aging; Appointment; base; Behavioral; Brain; Clinic; Cognitive; cognitive change; cognitive neuroscience; Cognitive Science; Comprehension; Dementia; Effectiveness; Elderly; Employee Strikes; Event; frontal lobe; Goals; Health; Hobbies; improved; Individual; Individual Differences; Instruction; interest; Intervention; Laboratories; Lateral; Learning; Life; long term memory; Longevity; Measures; Memory; memory retention; mental representation; Methods; Mind; movie; neuroimaging; Neurologic; neuropsychological; Pattern; Perception; Performance; Psychometrics; Research; response; Short-Term Memory; standard measure; Testing; tool; Training; Update; young adult
Project start date: 2008-08-01
Project end date: 2013-06-30
Budget start date: 15-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01AG031150-04 (2011): $296516
STUDIES OF THE RECIPROCAL RELATIONSHIP BETWEEN LEPTIN AND FAT
M Jeffrey, Professor
Rockefeller Universitycity: New York country: United States (us)
Grant 5R01DK041096-21 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Leptin is an adipocyte hormone that functions as the afferent signal in a negative feedback loop that regulates adipose tissue mass. As a key element of this feedback loop, leptin both responds to changes in adipose tissue mass and in turn modulates the size of the adipose depot. This application proposes a set of experiments that seek to elucidate the molecular mechanisms that are responsible for this reciprocal relationship between leptin and adipose tissue mass. In the first set of experiments, we propose elucidate the molecular mechanisms that control leptin gene expression. Leptin plasma and RNA levels can vary several hundred fold between the fasted and obese states and the transcriptional mechanisms responsible for its adipose tissue specific expression and this quantitative regulation are not known. Leptin is expressed at significantly higher levels in vivo vs. in vitro making it necessary to study leptin gene expression using transgenic mice. We have used an in vivo luciferase imaging system to localize the cis elements necessary for tissue specific and quantitative regulation to between -22 kB and +18 kB of the leptin gene. We propose further experiments to test a set of promoter deletions to map the cis elements and trans factors regulating leptin expression as a prelude to defining the relevant signal transduction pathway. We hypothesize that leptin is regulated by a lipid sensing system and, if true, these experiments could lead us to understand how intracellular lipid content is sensed and read out by the leptin gene, In the second set of experiments, we will explore the mechanism by which changing leptin levels control adipose tissue mass. While leptin deficient obese mice show a massive increase in the number of fat cells, the factors regulating fat cell production are largely unknown. We have recently identified an adipocyte stem cell that is capable of reconstituting a fat depot and correcting the metabolic abnormalities of fat deficient lipodystrophic mice. We now propose to further characterize this cell type in vivo and in vitro as a prelude to studies of the effects of leptin on the growth and development of this novel cell type. We also propose to study adipose tissue development by employing an ES cell complementation method that we have developed. In this method, wild type ES cells are injected into blastocysts of lipodystrophic animals. In the resulting chimaeras, the ES cells are the sole source of adipose tissue. This technique will allow us to titrate the number of ES cells to define the minimal clone size required for development of the adipose mass, results which will have important implications for our understanding of the ability of adipose tissue precursors to reconstitute adipose tissue. This method also provides a robust and efficient means for studying the role of specific gene products that will be identified in the other experiments in regulating adipose tissue development and function. Obesity is associated with Type II diabetes, hypertension, hyperlipidemia and hepatic steatosis and represents a major public health problem (1). Leptin, an adipocyte hormone, regulates adipose tissue mass as part of a feedback loop and a fuller understanding of the elements of this system could have important implications for the pathophysiology and treatment of obesity. In this application, we propose to address two unanswered questions in leptin physiology. What controls the amount of leptin that is produced in the lean vs. obese state? How do changes in leptin concentration in turn regulate adipose tissue mass?
Keywords: Address; adipocyte differentiation; Adipocytes; Adipose tissue; Adult; Animals; Automobile Driving; Biochemical; Biological Assay; blastocyst; Body Weight decreased; Cell Separation; cell type; Cells; Chimera organism; Data; Development; Diet; DNA Polymerase III; DNA Sequence; Elements; embryonic stem cell; ES Cell Line; falls; Fasting; Fatty acid glycerol esters; Fatty Liver; Feedback; feeding; Functional disorder; Gene Expression; Genes; Growth and Development function; Health; Hormones; Hyperlipidemia; Hypertension; Image; In Vitro; in vivo; Informatics; Knock-out; Lead; Leptin; lipid biosynthesis; Lipids; Luciferases; Maps; Mediating; Metabolic; Methods; Molecular; molecular marker; Molecular Profiling; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; novel; novel strategies; null mutation; Obese Mice; Obesity; obesity treatment; Phenocopy; Physiology; Plasma; Production; Promotor (Genetics); Proteins; public health medicine (field); Reading; reconstitution; Regulation; Reporter; Repression; research study; response; RNA; Role; Series; Signal Transduction; Signal Transduction Pathway; small hairpin RNA; Source; stem cell population; Stem cells; System; Techniques; Testing; Tissues; transcription factor; Transgenic Mice
Relevance: Obesity is associated with Type II diabetes, hypertension, hyperlipidemia and hepatic steatosis and represents a major public health problem(1). Leptin, an adipocyte hormone, regulates adipose tissue mass as part of a feedback loop and a fuller understanding of the elements of this system could have important implications for the pathophysiology and treatment of obesity. In this application, we propose to address two unanswered questions in leptin physiology. What controls the amount of leptin that is produced in the lean vs. obese state? How do changes in leptin concentration in turn regulate adipose tissue mass?
Project start date: 1989-09-20
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01DK041096-21 (2011): $360261
5R01DK041096-20 (2010): $401544
SELF-ADMINISTERED CBT FOR IBS: A MULTICENTER TRIAL
M Jeffrey
State University Of New York At Buffalocity: Buffalo country: United States (us)
Grant 5U01DK077738-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Irritable bowel syndrome (IBS) is a chronic, prevalent, often disabling, GI disorder for which there is no reliable and satisfactory medical option for its full range of symptoms (abdominal pain, bowel dysfunction). An accumulating body of evidence indicates that a specific psychosocial treatment called cognitive behavioral therapy (CBT) is associated with significant reductions in IBS symptoms and related difficulties. Despite its apparent efficacy, CBT´s clinical effectiveness (i.e., its generalizability, feasibility, cost effectiveness) has not been adequately established due partly to its duration, cost, and limited accessibility. As the "second generation" of IBS treatments undergo development and validation, it has become increasingly clear that efficacy demonstration is a necessary but not sufficient condition of treatment viability. In a pilot study funded under NIDDK´s R03 mechanism, we addressed these problems by developing a briefer, largely self administered version of CBT that requires only 4, I hr clinic visits. Our RCT data showed that a 10 session version of CBT can be translated into a 4 session version without compromising patient acceptability or short term efficacy. It is unclear whether treatment effects are maintained long term (out to 12 months), due to theoretical change mechanisms (vs. nonspecific factors common across different forms of therapy), are more pronounced among specific subgroups of patients, or, generalize to a large sample of Rome III diagnosed patients treated by different investigative sites. We seek to address these questions by conducting a larger, more definitive, multisite RCT that will recruit from 3 treatment sites 480 patients with moderate to severe IBS and assess their acute and long term response to brief (4 session) CBT, extended (10 session) CBT, or a credible attention placebo. We will use the first year to develop a clinical infrastructrue [sic] to ensure the success and integrity of the proposed trial. In the short term, a successful trial will lend empirical validation to a self administered version of CBT that retains the efficacy of standard CBT but is more transportable, accessible to patients outside of research protocols, and less costly to deliver. In the long term, we hope to show that a self guided behavioral treatment program is an effective and efficient treatment delivery system that can enhance the quality of patient care, improve clinical outcomes, and decrease the economic and personal costs of one of the most prevalent and intractable GI disorders. The primary goal of the proposed trial is to assess the short- and long-term efficacy of cognitive behavior therapy (CBT) for irritable bowel syndrome using two treatment delivery systems (self administered, therapist administered). Secondary aims seek to specify the conditions under which CBT may (or may not) achieve its effects (moderator questions), why and how these effects are achieved (mediator questions) and at what economic cost. Long term project goals are to develop an effective self-administered behavioral treatment program that can enhance the quality of patient care, improve clinical outcomes, and decrease the economic and personal costs of one of the most prevalent and intractable GI disorders
Keywords: Abdominal Pain; Acute; Address; Aftercare; Area; Attention; base; Behavior Therapy; Behavioral; Belief; Characteristics; Chronic; Client satisfaction; Climacteric; Clinic Visits; Clinical; Clinical effectiveness; Clinical Trials; Cognitive; Cognitive Therapy; Control Locus; cost; cost effective; cost effectiveness; Coupled; Data; Development; Diagnosis; Direct Costs; Distress; Economic Burden; economic cost; Economics; effective therapy; Ensure; Etiology; Expectancy; Facilities and Administrative Costs; Feces; follow-up; Functional disorder; Funding; Gastrointestinal Diseases; Generations; Goals; Healthcare; Healthcare Systems; Human; improved; Intestines; Irritable Bowel Syndrome; Mediating; Mediator of activation protein; Medical; Motivation; Multi-Institutional Clinical Trial; Multicenter Trials; novel; Outcome; Patient Care; Patients; Phase; Pilot Projects; Placebos; Protocols documentation; psychologic; psychological distress; psychosocial; Quality of life; Recruitment Activity; Relative (related person); Research; Research Infrastructure; response; Rome; Sampling; Self Efficacy; Self-Administered; Severities; Site; Subgroup; success; Symptoms; System; Testing; theories; Therapeutic; To specify; Translating; treatment effect; Treatment outcome; treatment program; treatment response; treatment site; Validation
Project start date: 2008-05-15
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5U01DK077738-04 (2011): $1151658
ENDOGENOUS NEUROPROTECTION IN GLAUCOMA
M Jeffrey, Associate Professor Of Neurosu
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R01EY018607-04 from National Eye Institute
Abstract: Glaucoma affects millions in the US and is the second leading cause of blindness worldwide. While surgical and pharmacologic approaches to reduce intraocular pressure can be beneficial, a recently convened NEI strategic planning group explicitly recommended focused research on retinal ganglion cell neuroprotection. One novel approach in this regard is the activation, by preconditioning, of robustly powerful survival mechanisms endogenous to the cell. We were the first to demonstrate in rodents that brief exposures to noninjurious ischemia or hypoxia promote near complete protection of the retina from ischemic injury. We now show in a mouse model of experimental glaucoma that long-lasting phenotypic changes induced by repetitive preconditioning with hypoxia, prior to intraocular hypertension, can prevent ganglion cell death. Studies proposed herein will utilize inducible and retina-specific knockout and transgenic mice to begin to elucidate the mechanistic basis of this innate protective response we have termed glaucoma tolerance. Specific Aim 1 Elucidate the role of the hypoxia-inducible transcription factor HIF-11 in mediating changes in gene expression responsible for glaucoma tolerance. Hypothesis Ganglion cell protection following repetitive hypoxic preconditioning results from a unique expression profile for HIF-11 that leads to the long-lasting expression of heme oxygenase-1 and other survival-promoting HIF-11 gene targets. Specific Aim 2 Determine how nitric oxide modulates the ability of repetitive hypoxic preconditioning to promote glaucoma tolerance. Hypothesis Activation of the constitutive nitric oxide synthase isoforms by repetitive hypoxic preconditioning is necessary for induction of a long-lasting cytoprotective phenotype by facilitating HIF-11-mediated and CREB-mediated transcription of cytoprotective genes. Specific Aim 3 Establish the mechanisms whereby glaucoma tolerance is achieved as a result of hypoxic preconditioning-induced activation of pAkt (protein kinase B)-dependent survival pathways. Hypothesis Repetitive hypoxic preconditioning promotes pAkt stabilization and, subsequently, the prolonged phosphorylation of several anti-apoptotic effectors that contribute to glaucoma tolerance. The endogenous mechanisms of ganglion cell protection identified in this research program may provide novel therapeutic targets for preventing or reducing optic neuropathy in glaucoma. Ganglion cell death in glaucoma is responsible for devastating vision loss in millions of individuals. Our work provides a new approach to ganglion cell protection Applying stress stimuli that activate endogenous mechanisms of gene expression to promote ganglion cell survival. Elucidation of the molecular basis of these innate cytoprotective pathways will yield a unique category of prevention and treatment strategies for the high-risk glaucoma population
Keywords: Affect; AKT; Akt protein; Apoptotic; base; Blindness; Blood Pressure, High; c-akt protein; Categories; Cell Death; Cell Protection; Cell Survival; Cell Viability; Cells; Cranial Nerve II Diseases; Cranial Nerve II Disorder; CREB; CREB1; CREB1 gene; Cytoprotection; Disorder of the optic nerve; EC 1.14.13.39; EDRF Synthase; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Growth Factor Synthase; Endothelium-Derived Relaxing Factor; Exposure to; Expression Profiling; Expression Signature; gangliocyte; ganglion cell; Ganglion Cells (Retina); Gene Expression; Gene Targeting; Gene Transcription; Genes; Genetic Transcription; Glaucoma; glaucomatous; Guanylyl Cyclase-Activating Factor Synthase; Haem Oxygenase; Heme Oxygenase (Decyclizing); heme oxygenase-1; Heme, hydrogen-donor[{..}]oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating); hemeoxygenase 1; high risk; HO-1 enzyme; HO1; HO2; HSP32; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; Hypoxia; Hypoxic; Individual; Injury; Intraocular Pressure; Ischemia; Isoforms; Knockout Mice; L-Arginine, NADPH[{..}]oxygen oxidoreductase (nitric-oxide-forming); Mammals, Rodents; Mediating; Mice, Knock-out; Mice, Knockout; molecuar profile; Molecular; Molecular Fingerprinting; Molecular Profiling; molecular signature; Mononitrogen Monoxide; mouse model; NADPH-Diaphorase; Names; necrocytosis; Neural-Optical Lesion; neuroprotection; new approaches; new therapeutic target; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide, Endothelium-Derived; Nitric-Oxide Synthetase; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; NO Synthase; novel approaches; novel strategies; novel strategy; Null Mouse; Ocular Tension; Operation; Operative Procedures; Operative Surgical Procedures; Optic Nerve Diseases; optic nerve disorder; Optic Neuropathy; Oxygen Deficiency; pathway; Pathway interactions; Phenotype; Phosphorylation; Physiologic Intraocular Pressure; PKB protein; Population; preconditioning; prevent; preventing; Prevention strategy; Preventive strategy; Principal Investigator; programs; Programs (PT); Programs [Publication Type]; Protein Isoforms; Protein Kinase B; Protein Phosphorylation; protein-serine-threonine kinase (rac); proto-oncogene protein akt; proto-oncogene protein RAC; Proto-Oncogene Proteins c-akt; rac protein kinase; RAC-PK protein; related to A and C-protein; Research; response; Retina; retinal ganglion; Retinal Ganglion Cells; RNA Expression; Rodent; Rodentia; Rodentias; Role; Second Cranial Nerve Diseases; second cranial nerve disorder; social role; Stimulus; Strategic Planning; Stress; surgery; Surgical; Surgical Interventions; Surgical Procedure; Targetings, Gene; Transcription; transcription factor; Transcription, Genetic; Transgenic Mice; treatment strategy; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Work
Project start date: 2008-02-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01EY018607-04 (2011): $338580
M Jeffrey, Assistant Professor
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5R01DA024680-04 from National Institute On Drug Abuse
Abstract: Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting. Also, ghrelin stimulates food intake, decreases energy expenditure, and induces obesity when present in high concentrations. Ghrelin´s actions are mediated by interaction with its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), which has a well-defined, discrete pattern of expression within the brain. This includes a high degree of expression in dopamine-containing neurons within a part of the brain known as the ventral tegmental area (VTA). These dopaminergic VTA neurons have been highly studied due to their involvement in brain reward circuits, such as those associated with addiction. The current application provides a series of studies designed to increase our understanding of the involvement of ghrelin in promoting reward- seeking behaviors and the role of the VTA in ghrelin action. In particular, the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and cocaine will be investigated. To accomplish this, unique mouse models in which either expression of the ghrelin receptor has been deleted or the functioning of the ghrelin receptor has been blocked by the administration of a specific antagonist will be used. These mice will be subjected to a battery of tests that will allow us to determine the effect of genetic and pharmacological blockade of ghrelin signaling pathways on food-reinforced and cocaine-reinforced reward-seeking behaviors. Also, a unique mouse model in which ghrelin receptor expression can be selectively targeted to dopaminergic VTA neurons will be used in order to investigate the sufficiency of ghrelin´s engagement of these particular neurons for its actions on reward behaviors and body weight. This selective targeting will involve state-of-the- art neuroanatomical and transgenic techniques. It is hoped that these studies will result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction. PUBLIC HEALTH RELVANCE The experiments proposed in this study have been designed to investigate the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and addictive drugs such as cocaine. It is hoped that these studies will eventually result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction
Keywords: Acute; addiction; Affect; Behavior; Body Weight; Brain; Brain Part; Characteristics; Chronic; Cocaine; Complement; design; Diet; Dopamine; dopaminergic neuron; drug of abuse; drug seeking behavior; Eating; Energy Metabolism; Fasting; Fatty acid glycerol esters; Food; Food deprivation (experimental); Genetic; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; Health; Homeostasis; Hormones; Hunger; Knockout Mice; Mediating; Metabolic; Modeling; Moods; motivated behavior; mouse model; Mus; Neurons; Obesity; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Prader-Willi Syndrome; preference; Property; receptor; receptor expression; Research Design; research study; Resistance; response; reward circuitry; Rewards; Role; Series; Signal Pathway; Signal Transduction; System; Techniques; Testing; Transgenic Organisms; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Weight maintenance regimen
Project start date: 2008-06-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01DA024680-04 (2011): $305791
Sponsored Links Excellgen http://Excellgen.com
CARP: ANGIOGENIC GENE THERAPY IN DIABETIC WOUNDS
M Jeffrey, Professor
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5R01DK065656-08 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Gene expression profiling of murine wounds revealed marked, sustained induction of cardiac ankyrin repeat protein (CARP, ankrdl), with diminished expression in diabetic mice. Overexpression of CARP in wounds by adenoviral gene transfer produces a remarkable increase in neovascularization and thereby enhances wound healing. Under the previous aims, we established these effects in several animal models and showed that CARP induction occurs in microvascular endothelial cells (MVEC), in part, through TGF-IS mediated activation of a p38 kinase pathway. CARP also protects endothelial cells from doxorubicin-mediated apoptosis, and it enhances MVEC migration, not proliferation. To avoid overlap, the proposed studies will concentrate on gain-of-function aspects of CARP. The proposed studies will extend the original aims by delineating the CARP activation pathway as well as identifying its binding partners and direct transcriptional targets. We will test the hypothesis that hyperglycemic, oxidative stress is related to CARP induction. Experiments will determine the influence of TNF-a and possible convergent signal mechanisms. Binding partners in vascular cells will be identified by yeast two- hybrid, protein microarray, and tandem affinity purification methods. EMSA and ChIP analysis will be used to identify the transcriptional activators in MVEC and smooth muscle cells (SMC). Expression profiling will be expanded to identify key targets in both MVEC and SMC. CARP has been suggested to be a mediator of mechanical stress in cardiac muscle. Experiments will test the significance of CARP´S putative nuclear and cytoplasmic interaction sites in SMC and MVEC by deletion and mutation of discrete, functional domains of the protein, read out as migratory and stress responses of targeted cells. Partners for these sites will be identified. The clinical relevance of CARP will be investigated in a series of rat healing studies in diabetic and ischemic wounds with a novel gene delivery system. These experiments will define the optimal dose for repair, and investigate the role of CARP in vessel regression and stabilization. If the benefits and mechanisms of this form of wound therapy are validated, they could lead to the development of CARP as a novel therapeutic and to the discovery of factors that mediate CARP-enhanced neovascularization
Keywords: Abbreviations; acronyms; Adenovirus Protein; Affect; Affinity Chromatography; angiogenesis; Angiogenic Proteins; Angiopoietin-1; Animal Model; Ankyrin Repeat; Apoptosis; Area; Binding (Molecular Function); biological adaptation to stress; Blood capillaries; Blood Vessels; capillary; Cardiac; cell motility; Cells; clinically relevant; connective tissue growth factor; Defect; Deletion Mutation; Development; diabetic; Diabetic mouse; Diabetic wound; diabetic wound healing; Dose; Doxorubicin; EGF gene; EMSA; Endothelial Cells; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Exhibits; extracellular; Fibroblast Growth Factor 2; Firefly Luciferases; gain of function; Galactosidase; gene delivery system; Gene Expression Profiling; Gene Targeting; gene therapy; Gene Transfer; Genes; Genetic Transcription; Glyceraldehyde; Green Fluorescent Proteins; Healed; healing; Human; hybrid protein; Hyperglycemia; improved; Inflammatory; inorganic phosphate; Internal Ribosome Entry Site; LacZ Genes; Lead; MAP Kinase Gene; MAPK14 gene; Mechanical Stress; Mediating; Mediator of activation protein; Methods; Mitogen-Activated Protein Kinases; Molecular Profiling; Morphology; Mothers; Mus; Mutation; Myocardium; neovascularization; novel; novel therapeutics; Nuclear; overexpression; Oxidative Stress; Oxidoreductase; Pathway interactions; Phase; Phenotype; Phosphotransferases; Platelet-Derived Growth Factor; Polyvinyl Alcohol; programs; Protein Activation Pathway; protein expression; Protein Kinase; Protein Microchips; Protein Overexpression; Protein S; Proteins; Rattus; Reading; receptor; repaired; Research Personnel; research study; Ribonucleases; RNA; Role; Series; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Smooth Muscle Myocytes; Tertiary Protein Structure; Testing; TNF gene; Transcription Coactivator; transcription factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vascular blood supply; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular remodeling; vasculogenesis; vessel regression; wound; Wound Healing; yeast two hybrid system; Yeasts
Project start date: 2003-09-30
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R01DK065656-08 (2011): $304914
GAIT INSTABILITY IN THE ELDERLY WITH INCREASED FALL RISK
M Jeffrey, Director
Tel-aviv Sourasky Medical Centercity: Tel Aviv country: Israel (is)
Grant 5R01AG014100-09 from National Institute On Aging
Abstract: Falls are a leading cause of morbidity and mortality among older adults. Although gait and mobility are generally considered over-learned and automatic functions, recent findings highlight the potential importance of cognitive function in fall risk and gait variability. Preliminary work suggests that specifically higher-level cognitive function influences gait variability and fall risk, but the relationships between cognitive function and gait variability have not been well-studied. For example, it is not clear if or why idiopathic elderly fallers increase stride-to-stride variability when they perform a secondary task while walking. Two studies of cognitive function, gait variability, and fall risk will be performed. These studies of multiple aspects of cognitive function and gait, especially under "dual tasking" conditions, should demonstrate that gait, in particular gait variability, is related to and may rely on executive function and attention. Specifically, we will test the following hypotheses 1) Executive function and attention influence gait variability and fall risk in older adult, "idiopathic" fallers. Using computerized neuropsychological testing, we aim to identify, for the first time, the specific components of cognitive function that modulate gait variability, fall risk, and dual-tasking gait abilities among community living older adults (fallers and non-fallers) and healthy young adults. 2) Changes over time in gait variability parallel changes in cognitive function. A three-year prospective study of community living older adults will be performed to identify which changes in cognitive function over time are associated with changes in gait and fall risk, and to determine whether the assessment of cognitive function and gait variability enhances the prospective identification of future fallers. This prospective study will allow us to document the natural history of two physiologic systems that commonly decline in older adults, to answer key questions regarding the nature of gait and fall risk in older adults and their dependence on cognitive function, and to set the stage for for new ways of treating gait disturbances and reducing fall risk
Keywords: Abnormal gait; Address; adult youth; advanced age; Affect; Age; Aged 65 and Over; Aging; Attention; Clinic; Clinical; clinical relevance; clinically relevant; Cognitive; cognitive function; community living; computerized; Condition; Cross Sectional Analysis; Cross-Sectional Analyses; Cross-Sectional Studies; Cross-Sectional Survey; Dependence; Dimensions; Disease Frequency Surveys; Elderly; Elderly, over 65; elders; executive control; executive function; falls; Fractals; Future; Gait; Gait abnormality; Gait disorder; Gait disturbances; geriatric; health care economics; healthcare economics; improved; indexing; Individual; insight; intervention development; intervention program; Investigators; late life; later life; Learning; Measurement; Measures; Methods; Monitor; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Muscle function; National Institutes of Health; National Institutes of Health (U.S.); Natural History; Nature; neural control; neural regulation; Neuropsychologic Tests; neuropsychological; Neuropsychological Tests; neuroregulation; NIH; Numbers; older adult; older person; pathway; Pathway interactions; Patients; Personal Satisfaction; Persons; Physiologic; Physiological; Play; programs; Programs (PT); Programs [Publication Type]; prospective; Prospective Studies; QOL; Quality of life; Regulation; Research; Research Personnel; Researchers; Risk; Role; Senescence; senescent; senior citizen; Social Functioning; social role; Speed; Speed (motion); Staging; Standards; Standards of Weights and Measures; System; System, LOINC Axis 4; Testing; therapy development; Time; treatment development; United States National Institutes of Health; Walking; well-being; Work; young adult
Project start date: 1997-09-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2011
5R01AG014100-09 (2008): $127953
CELL BIOLOGY OF ENTEROVIRUS INFECTION IN POLARIZED EPITHELIAL CELLS
M Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Grant 5R01AI072490-04 from National Institute Of Allergy And Infectious Diseases
Abstract: Enteroviruses are transmitted by the fecal-oral route, and must cross the intestinal mucosa to initiate infection. The intestines are lined by polarized epithelial cells, with distinct apical and basolateral surfaces; intercellular tight junctions prevent virus access to receptors on basolateral membranes. Many enteroviruses, including many coxsackie B viruses (CBV) and echoviruses (EV), appear to have evolved independently to bind to decay accelerating factor (DAF), a molecule expressed on the surface of polarized epithelium. We believe that these viruses use DAF to interact with epithelial cells in the intestinal lumen. DAF does more than simply provide a site for virus attachment. We recently found that it initiates at least two intracellular signaling pathways required for CBV entry and infection in polarized cells activation of Abl kinase leads to actin rearangements and virus movement to the tight junction, where interaction with the coxsackievirus and adenovirus receptor (CAR) initiates the uncoating process that releases viral RNA; activation of Fyn kinase triggers virus internalization in caveolar vesicles, and delivery to the endoplasmic reticulum (ER) where uncoating is completed before replication ensues. We have more recently determined that virus entry from the tight junction is linked to the internalization of a tight junction protein, occludin, and that both virus entry and occludin internalization occur by a process that combines aspects of caveolar endocytosis with features characterisitc of macropinocytosis. These results suggest that infection of polarized cells is a complex process likely to involve distinctive cell biological mechanisms. We propose three sets of experiments to examine the cell biology of infection in polarized epithelium. 1. We will define the pathway by which DAF-binding EV enter polarized epithelium, following the entry of labeled virus, and using specific inhibitors (drugs, siRNAs) to dissect the underlying cellular processes. 2. We will determine the function of actin rearrangements and changes in microvillus architecture during virus entry, and identify the mechanism by which actin reorganization is initiated in response to virus-DAF interaction. 3. We will screen a siRNA library to identify signaling molecules required for CBV entry into polarized epithelium, and define the role of specific signaling molecules in the process of infection. Enteroviruses are the major cause of viral meningitis, and the second major cause of myocarditis in the US, and interaction with polarized epithelium is the first step in infection. Understanding the special mechanisms by which enteroviruses infect polarized cells will reveal new potential drug targets
Keywords: Actins; adenovirus receptor; Apical; Architecture; basolateral membrane; Binding (Molecular Function); Biological; Capsid; Caveolae; CD55 Antigens; Cell membrane; Cell physiology; Cells; Cellular biology; cellular microvillus; Complex; Coxsackie B Viruses; Coxsackie Viruses; Cytoskeleton; Data; DNA Sequence Rearrangement; Drug Delivery Systems; Echo Viruses; Endocytosis; Endoplasmic Reticulum; Enterovirus; Enterovirus Infections; Epithelial Cells; Epithelium; Event; Guanosine Triphosphate Phosphohydrolases; Health; Human; Human Echovirus 6; Infection; inhibitor/antagonist; Intervention; intestinal epithelium; Intestinal Mucosa; Intestines; Label; Libraries; Link; Movement; Myocarditis; occludin; Oral; pathogen; Pathway interactions; Penetration; Pharmaceutical Preparations; Phosphotransferases; polarized cell; prevent; Process; Proteins; receptor; research study; response; Role; Route; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Surface; Tight Junctions; Vesicle; Viral meningitis; viral RNA; Virus
Project start date: 2008-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01AI072490-04 (2011): $388892
5R01AI072490-03 (2010): $0
5R01AI072490-02 (2009): $387673
1R01AI072490-01A2 (2008): $326591
GENOMIC ANALYSIS OF TUMOR CONTEXT VULNERABILITIES IN HUMAN METASTATIC MELANOMA
M Jeffrey, President And Scientific Director
Translational Genomics Research Instcity: Phoenix country: United States (us)
Grant 5U01CA129447-05 from National Cancer Institute
Abstract: Despite decades of research, metastatic malignant melanoma remains an incurable disease. Only a minority of patients diagnosed with metastatic melanoma show a clinical response to chemotherapy, while still fewer are cured; the 5-year survival rate for patients with disseminated disease ranges from 5-18%. The focus and underlying goal of this project is to identify specific genetic changes in melanoma, confirmed through both functional genomic screening and in vivo validation, which provide a context of genetic vulnerability that can be exploited in advanced stage melanoma. Specifically, we are proposing to undertake a high-throughput functional RNA interference (RNAi) screen to systematically identify genes that mediate melanoma cell sensitivity (Specific Aim 1). We will subsequently validate the role of these genes (Specific Aim 2) by confirming siRNA-mediated gene knockdown in vitro, characterizing protein expression in human melanomas using tissue microarrays (TMAs), performing high-content mechanistic assays to elucidate the mechanism by which these genes mediate melanoma cell sensitivity in vitro, and evaluating the effectiveness of inhibiting these genes in vitro in combination with the selecting agent. Lastly, we will evaluate whether our validated genetic targets can add to molecularly-informed combination therapies in vivo against xenograft models of melanoma (Specific Aim 3). We hypothesize that this functional-based genomic approach will identify the context of genetic perturbations associated with tumor progression that are critical to rendering melanoma cells more resistant to chemotherapy. We speculate that these validated genes could facilitate the combined targeting of these tumor-context vulnerabilities and could be of direct relevance to clinical exploitation. Relevance The long-term prognosis for patients diagnosed with advanced stage melanoma is dismal, with a five-year survival rate ranging from 5-18%. The proposed research aims to identify genetic vulnerabilities acquired by metastatic melanoma cells that may be exploited to improve the effectiveness of clinical intervention in this disease
Keywords: base; Biological Assay; cancer cell; Candidate Disease Gene; Cell Line; Cells; chemotherapy; Clinical; Clinical effectiveness; Combined Modality Therapy; Data; Data Analyses; Diagnosis; Disease; Dose; Drug Sensitization; Effectiveness; Evaluation; Event; functional genomics; Functional RNA; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Heterogeneity; Human; Image; improved; In Vitro; in vivo; Intervention; Mediating; melanoma; Melanoma Cell; Metastatic Melanoma; Minority; Modeling; Mutation; outcome forecast; Patients; Pharmaceutical Preparations; protein expression; Research; Resistance; response; RNA Interference; RNA library; Role; Screening procedure; Small Interfering RNA; Staging; Survival Rate; temozolomide; Testing; Time; Tissue Microarray; tumor; tumor progression; Validation; Western Blotting; Xenograft Model
Project start date: 2007-07-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5U01CA129447-05 (2011): $405722
RECEPTORS AND SIGNALS IN COXSACKIEVIRUS PATHOGENESIS
M Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Grant 5R01AI052281-10 from National Institute Of Allergy And Infectious Diseases
Abstract: Coxsackie B viruses (CBV) interact with two receptors to initiate infection. All CBV initiate infection by attaching to the coxsackievirus and adenovirus receptor (CAR); many CBV isolates also bind to a second receptor, human decay accelerating factor (DAF). CBV, like other enteroviruses, are transmitted by the fecal-oral route in humans, and initiate infection by crossing the intestinal mucosa; however, CAR is not expressed on the apical surface of the polarized epithelial cells that line the intestinal lumen. In the first funding period of this grant, we have found that DAF is essential for infection of polarized cells. DAF permits virus to attach to the cell surface, but more importantly, it induces multiple intracellular signals that are required for virus uptake into the cell. We have found that additional virus-induced signals initiate non-apoptotic cell death by activating calcium-dependent proteases (calpains). Based on these observations, we propose a new series of experiments, focused on virus interaction with DAF, the role of DAF in infection by the enteral route, and the mechanisms and importance of calcium-mediated death signals. 1. We will define the site on the virus surface that permits attachment to DAF, and the site on the DAF molecule responsible for interaction with virus, using site-directed mutagenesis to test a model of the virus-DAF complex recently derived from cryo-em experiments. 2. We will determine whether DAF expression on the epithelial cell surface is important for in vivo infection by the enteral route, using transgenic mice expressing human DAF on intestinal epithelium. 3. We will define the signaling pathway that leads to necrotic cell death in cultured intestinal epithelium, determine whether calpain activation contributes to the pathogenesis of myocarditis and pancreatitis in infected animals, and test whether calpain inhibitors reduce the severity of disease. Relevance Enteroviruses are the major cause of viral meningitis, and the second major cause of myocarditis in the US. Understanding how virus interacts with its intestinal receptor as it initiates infection, and understanding the mechanisms of virus-induced cell death, may provide new targets for therapeutic intervention
Keywords: adenovirus receptor; Animal Testing; Apical; base; Binding (Molecular Function); Calcium; Calpain; calpain inhibitor; Cardiac; CD55 Antigens; Cell Adhesion Molecules; Cell Death; Cell Line; Cell physiology; Cell surface; Cells; Cessation of life; Complex; Coxsackie B Viruses; Coxsackie Viruses; Cross Infection; Cryoelectron Microscopy; Data; Development; Enteral; Enterovirus; Epithelial Cells; Event; Funding; Grant; Human; Image Reconstructions; In Vitro; in vivo; Infection; intestinal epithelium; Intestinal Mucosa; Intestines; Knockout Mice; Lead; Maps; Mediating; Modeling; Mus; Mutation; Myocarditis; Myocardium; Necrosis; Oral; Pancreas; Pancreatitis; Pathogenesis; Peptide Hydrolases; polarized cell; Predisposition; programs; Proteins; Publishing; receptor; Receptor Signaling; Research Personnel; research study; RNA; Role; Route; Series; Severity of illness; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Staging; Structural Models; Structure; Surface; Testing; Therapeutic Intervention; Tight Junctions; Time; Tissues; Transgenic Mice; transmission process; Tropism; uptake; Viral meningitis; Virion; Virus; Virus Diseases; virus pathogenesis; Virus Receptors; Work
Project start date: 2002-09-20
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5R01AI052281-10 (2011): $395409
LONG-ACTING HIV THERAPY FOR INJECTION DRUG USERS
M Jeffrey, Division Chief/ Professor
Drexel Universitycity: Philadelphia country: United States (us)
Grant 5R01DA029663-02 from National Institute On Drug Abuse
Abstract: Combination antiretroviral therapy has provided many HIV-infected individuals with a near-normal life expectancy, provided they have access to care and can maintain strict lifetime adherence to the daily or more frequent treatment regimens. The most important factor in the virologic failure of an antiretroviral regimen is poor adherence of the patient to complete and proper dosing. HIV-infected IDUs face well-documented challenges to maintaining optimal adherence. Accordingly, this group, which represents approximately one- quarter of the U.S. HIV epidemic, has yet to derive the full benefits of the available antiretroviral therapies. Various interventions to improve antiretroviral drug adherence, ranging from counseling to directly-observed therapy and other structural interventions, have had only modest success. We propose a novel treatment strategy involving systemic administration of long-acting antiretroviral therapy as a means to ensure effective drug delivery and viral suppression in HIV-infected populations prone to poor drug-adherence. We propose a randomized, double-blind, placebo-controlled study of weekly subcutaneous treatment with the CCR5 monoclonal antibody PRO 140 in combination with a standard-of-care oral antiretroviral regimen. PRO 140 is uniquely suited for this use as it is the only HIV drug to demonstrate long-acting viral suppression without the need for slow IV infusion. Success in this pilot study would identify a new strategy for improving the care of HIV-infected IDUs and other vulnerable populations that are underserved by the current generation of antiretroviral medications. Positive results could catalyze this field and spur development and testing of other long-acting HIV drugs in this population. Combination antiretroviral therapy has provided many HIV-infected individuals with a near- normal life expectancy, provided they have access to care and can maintain strict lifetime adherence to the daily or more frequent treatment regimens. HIV-infected injection drug users (IDUs) face well-documented challenges to maintaining optimal adherence. Accordingly, this group, which represents approximately one-quarter of the HIV epidemic in the United States, has yet to derive the full benefits of the available antiretroviral therapies. We propose a novel treatment strategy involving systemic administration of long-acting antiretroviral therapy as a means to ensure effective drug delivery and viral suppression in HIV-infected populations prone to poor drug-adherence
Keywords: Adherence (attribute); AIDS/HIV problem; Alcohols; Anti-Retroviral Agents; Antibodies; antiretroviral therapy; base; Caring; CCR5 gene; Chronic Disease; Communities; Compliance behavior; Controlled Clinical Trials; Counseling; Development; Directly Observed Therapy; Disease; Doctor of Medicine; Dose; Double-Blind Method; Drops; Drug abuse; Drug Delivery Systems; Drug resistance; Drug usage; Drug user; Ensure; Epidemic; Face; Failure (biologic function); Generations; Health Services Accessibility; Highly Active Antiretroviral Therapy; HIV; HIV Infections; HIV therapy; Illicit Drugs; immune function; improved; Individual; Infection; Injecting drug user; innovation; Intervention; Intravenous; Intravenous infusion procedures; Life; Life Expectancy; Medicine; Mental Depression; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mortality Vital Statistics; National Institute of Drug Abuse; NIH Program Announcements; novel; open label; Oral; oral care; Oral Medicine; Patients; Perception; Pharmaceutical Preparations; Pilot Projects; Placebo Control; placebo controlled study; Population; Principal Investigator; PRO 140; programs; public health medicine (field); public health relevance; Race; Randomized; Regimen; Research; Research Personnel; response; Risk; Self Efficacy; Socioeconomic Status; subcutaneous; Subgroup; success; Testing; transmission process; treatment duration; Treatment Protocols; treatment strategy; United States; Vertical Disease Transmission; Viral; Viral Load result; Viremia; Virus; Vulnerable Populations
Relevance: Program Director/Principal Investigator (Last, First, Middle): Jacobson, Jeffrey M., M.D. Narrative: Public Health Significance Combination antiretroviral therapy has provided many HIV-infected individuals with a near- normal life expectancy, provided they have access to care and can maintain strict lifetime adherence to the daily or more frequent treatment regimens. HIV-infected injection drug users (IDUs) face well-documented challenges to maintaining optimal adherence. Accordingly, this group, which represents approximately one-quarter of the HIV epidemic in the United States, has yet to derive the full benefits of the available antiretroviral therapies. We propose a novel treatment strategy involving systemic administration of long-acting antiretroviral therapy as a means to ensure effective drug delivery and viral suppression in HIV-infected populations prone to poor drug-adherence
Project start date: 2010-04-01
Project end date: 2015-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-307
5R01DA029663-02 (2011): $715774
ROLE OF PAK KINASES IN SURVIVAL AND MOTILITY
M Jeffrey, Professor
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01GM048241-18 from National Institute Of General Medical Sciences
Abstract: Among the properties that distinguish tumor cells from normal cells are uncontrolled proliferation, invasion of other tissues, and resistance to apoptosis. Our long term goals are to understand how oncogenes, especially Ras, promote these properties. The major effector that Ras binds and activates is the Raf protein kinase, but critical transformation signals are mediated by direct binding to other effectors including phosphatidylinositol-3-OH kinase (PI 3-kinase). PI 3-kinase signals to Akt to inhibit apoptosis and to small GTPases such as Rac to promote cell invasion. Rac regulates a serine threonine protein kinase called Pak. Our studies provided the first evidence that Pak mediates cell transformation signals from Ras. In addition to its requirement for Ras transformation, we found that Pak stimulates cell survival by phosphorylating Raf-1 and causing it to translocate to mitochondria, bind Bcl-2 and phosphorylate the cell survival factor BAD. Pak also regulates cell motility through its effects on the actin cytoskeleton. We have been studying the role of Akt in cell migration and have implicated Pak in the process. Interestingly, the Akt1 and Akt2 isoforms have opposing roles in cell migration and regulation of Pak. We have found that Akt1 promotes motility and cell migration, while Akt2 inhibits cell migration and Pak activation. We hypothesize that Pak has central roles in survival and motility through its interactions with Raf-1 and Akt. We propose to (1) Identify the mechanisms underlying the effects of Pak on cell survival (2) Determine the mechanism responsible for the distinct effects of Akt1 and Akt2 on Pak and cell motility (3) Determine the roles of Pak and Akt in migration and survival of malignant Peripheral Nerve Sheath Tumors (MPNST) and the Schwann cells from which they originate Relevance to public health-Several properties distinguish cancer cells from normal cells, including the ability to invade surrounding tissues and resistance to programmed cell death. This grant proposes to study some of the genes that control cell death and invasion with the long term goal of understanding how the knowledge could be used to design better cancer therapies
Keywords: 1-Phosphatidylinositol 3-Kinase; Actins; anticancer therapy; Apoptosis; Apoptosis Pathway; ATP-protein phosphotransferase; ATP[{..}]1-phosphatidyl-1D-myo-inositol 3-phosphotransferase; Binding; Binding (Molecular Function); biological signal transduction; Body Tissues; cancer cell; Cancer Genes; cancer therapy; Cancer Treatment; Cancer-Promoting Gene; Cell Communication and Signaling; Cell Death; Cell Death, Programmed; Cell Locomotion; Cell Migration; cell motility; Cell Movement; Cell Protection; Cell Signaling; Cell Survival; cell transformation; Cell Viability; Cells; Cellular Matrix; Cellular Migration; Characteristics; Chimera; Chimera organism; Cytoprotection; Cytoskeletal System; Cytoskeleton; Data; design; designing; Disease model; disorder model; Dorsal; EC 2.7; Extracellular Signal-Regulated Kinase Gene; Feeds; Fibroblasts; gene product; Genes; glycogen synthase a kinase; Goals; Grant; hydroxyalkyl protein kinase; Immigrations; In-Migration; Intracellular Communication and Signaling; intracellular skeleton; Invaded; Investigators; Isoforms; Kinases; Knock-out; Knockout; Knowledge; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Peripheral Nerve Sheath Tumor; Malignant Schwannoma; MAP Kinase Gene; MAPK; Measures; Mediating; Mitochondria; mitochondrial; Mitogen-Activated Protein Kinase Gene; Modeling; Molecular Interaction; Monomeric G-Proteins; Monomeric GTP-Binding Proteins; Motility; Motility, Cellular; MPNST; necrocytosis; neoplastic cell; Neurilemma Cell; Neurilemmal Cell; Normal Cell; Oncogenes; Phosphatidylinositol 3-Kinase; Phosphatidylinositol-3-OH Kinase; Phosphoinositide 3-Hydroxykinase; phosphorylase b kinase kinase; Phosphorylation; Phosphotransferases; PI-3 Kinase; PI-3K; PI3-Kinase; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protein Isoforms; Protein Kinase; Protein Phosphorylation; Protein-Serine Kinase; Protein-Serine-Threonine Kinases; Protein-Threonine Kinase; Proteins; PtdIns 3-Kinase; Public Health; public health medicine (field); Regulation; Research Personnel; Researchers; Resistance; resistant; Role; Schwann Cells; Serine Kinase; Serine-Threonine Kinases; Signal Transduction; Signal Transduction Systems; Signaling; Small G-Proteins; Small GTPases; social role; Specificity; Testing; Threonine Kinase; Tissues; transformed cells; Transforming Genes; Transphosphorylases; tumor; Tumor Cell; Tumor Cell Line; tumor suppressor; Tumor Suppressor Proteins; Tumor-Derived; Type I Phosphatidylinositol Kinase; Type III Phosphoinositide 3-Kinase
Project start date: 1992-04-01
Project end date: 2012-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2012
5R01GM048241-18 (2010): $380457
Sponsored Links Excellgen http://Excellgen.com
ELASTIN AND COLLAGEN IN THE AGING PROCESS
M Jeffrey, Professor
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5R01AG006528-25 from National Institute On Aging
Abstract: Aging, growth and development bring about progressive changes in the capacity to repair and regenerate. The greatest economic costs come at the end of life as increasingly fragile skin and immobility conspire with ischemia and a delayed healing response to generate chronic wounds. This proposal combines efforts to understand age-related aspects of the regenerative and healing responses in four specific aims. First, the relative importance of the mesenchymal stem cell (MSC) in wound healing will be tested by adoptive transfer of marrow and by local administration of MSCs exchanged between young and old mice. Mouse strains with different regenerative capacities will also be compared. The next three aims relate to the role of the Wnt signal pathway. The second aim extends from preliminary observations of the enhanced regeneration of wounds in mice that contain a conditional FSP-cre/R.-cateninAex3 allele for stabilized li-catenin, the major mediator of canonical Wnt signaling. This regenerative phenotype will be studied in different types of wound models, and we will determine if MSCs from conditional expressors of stabilized R-catenin differ in their capacity to promote healing and regeneration. We will compare the capacity of stabilized li-catenin, MRL/"super-healer", and wild type mouse MSCs to modify the healing process by adding stem cells to the wound site. Aim three focuses on the role the Wnt pathway in MSC biology. We will determine if Wnt signaling is critical to the properties of the MRL.The fourth aim concentrates on the biological properties of FGF binding protein (FGF-BP). In impaired wounds, FGF-BP produces a remarkable expansion of granulation tissue, suggesting that availability of FGF is limited in chronic wound states such as ischemia. Since FGF-BP is reportely a direct target of IS-catenin, we will also examine FGF-BP expression in wounds of the MRL and stabilized li-catenin mouse. Normal and ischemic wounds from young and old rats will be compared for responses to FGF-BP supplementation by adenoviral gene transfer. The activity of FGF-BP will also be evaluated in vivo. These novel signal pathways may be able to convert the chronic wound into a normal wound as well as shift the equilibrium from repair to regeneration. Lay Summary Tissue regeneration and repair progressively decline with age. We will study how stem cells that come from the bone marrow respond to signals that can improves the speed and quality of healing
Keywords: Address; Adoptive Transfer; Affect; Age; age related; Aging; Aging-Related Process; Alleles; Animals; Appearance; base; Binding Proteins; Binding Sites; Biological; Bone Marrow; C-terminal; Cartilage; cell behavior; Chronic; Code; Collagen; comparative; Data; Development; economic cost; Elastin; Employee Strikes; end of life; Epidermis; Epithelial; Equilibrium; Extracellular Matrix; Fibroblast Growth Factor; Gene Expression Profiling; Gene Transfer; Genotype; Granulation Tissue; Growth and Development function; Growth Factor; Hair follicle structure; Healed; healing; Immunodeficient Mouse; Immunohistochemistry; Impaired wound healing; Implant; improved; In Situ Hybridization; In Vitro; in vivo; Injury; Ischemia; Laboratories; Maps; Marrow; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Messenger RNA; Metabolism; Modeling; Mouse Strains; Mus; N-terminal; Natural regeneration; normal aging; novel; Nuclear Translocation; overexpression; Pathway interactions; Phenotype; Porifera; postnatal; Process; programs; Property; protein expression; Proteins; Rattus; recombinase; regenerative; Relative (related person); repaired; Research Personnel; research study; response; Reverse Transcriptase Polymerase Chain Reaction; Role; Seeds; Signal Pathway; Signal Transduction; Site; Skin; Soil; Source; Speed (motion); stem; stem cell biology; Stem cells; Structure; Supplementation; System; Testing; Thick; Time; tissue regeneration; Tissues; Wild Type Mouse; wound; Wound Healing
Project start date: 1986-02-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R01AG006528-25 (2011): $248932
NANOPARTICLE INDUCED CIRCUIT EXCITATION
M Jeffrey, Professor
Rockefeller Universitycity: New York country: United States (us)
Grant 1R01GM095654-01A1 from National Institute Of General Medical Sciences
Abstract: A set of experiments is proposed to validate and further develop a new nanoparticle based technology, Nanoparticle induced Circuit excitation (NICE), for modulating the activity of cells remotely and non-invasively. A fundamental goal of biology is to understand the role of each cell type in a complex organism. The definitive test of cell function is to selectively turn on or off the activity of a single cell type in a living animal and examine the effect on physiological function. Recent tools, such as light activated ion channels such as channel rhodopsin, have pioneered the external control of membrane potential in genetically defined cells and established a new means for investigation by neuroscientists. However, these optical methods have practical disadvantages limiting their application including the need for surgical implantation of invasive fiber optics; the inability to stimulate cells in multiple anatomical regions simultaneously; and the difficulty of modulating multiple cell types in parallel. We address this challenge by using nanoparticles to activate defined cell populations remotely with radiowaves. Ferrous oxide coated with streptavidin is used to decorate cells, which express a biotin acceptor protein under the control of cell specific promoters. These same cells are engineered to also express TRPV1, a single component, temperature-sensitive ion channel that can detect small changes in temperature within the physiological range and by conformational change allow graded calcium entry. Exposing the metal coated cells to a defined electromagnetic field increases the local temperature and activates TRPV1 channels resulting in a Ca2+ current and cell activation. We have preliminary data that confirms the efficacy of this method in vitro and now propose to extend our studies to further validate the technology in vitro and to modulate in vivo functions such as hormone release and neural activity. We will also establish a means for combinatorial activation of different cells using a modified TRPV1 and nanoparticles fabricated from other metals that can be excited at different wavelengths. We will use this tool to examine the roles of specific peripheral and CNS cell populations in energy metabolism. We propose to develop this method in three stages 1) Validate the safety and utility of NICE in vitro and refine the methodology by decorating different cell types with distinct particles tuned to different wavelengths to activate ensembles of different cell populations in various combinations. 2) Establish the ability of NICE to modify hormone release to regulate glucose metabolism in diabetic animals in vivo. 3) Show that NICE can be used to stimulate action potentials in electrically excitable cells to modify behavior and use NICE to investigate the role of specific hypothalamic populations in (NPY and POMC) to control appetite. In time, NICE may be adapted for clinical uses, e.g induced pluripotent stem cells engineered to express NICE constructs may act as autografts to enable external control of cell function. These applications are distant but not inconceivable and the studies proposed may form the foundation for the clinical use of nanoparticles. This proposal aims to validate a novel technology, Nanoparticle Induced Circuit Excitation (NICE), for external, non-invasive activation of defined cell populations in living animals. We propose to apply this methodology to express insulin and thus control glucose in diabetic animals and to modulate feeding behavior by activating specific neural populations. The studies proposed in this application will thus validate the use of NICE and provide a foundation for the eventual use of nanoparticles in clinical settings
Keywords: Action Potentials; Address; Animals; Antibodies; Apoptosis; Autologous Transplantation; base; Basic Science; Behavior; Binding (Molecular Function); Biology; Biotin; blood glucose regulation; Brain; Calcium; Cell physiology; Cell surface; cell type; Cells; cellular engineering; Clinical; combinatorial; Communities; Complex; Coupled; Cultured Cells; Data; Desire for food; diabetic; Diabetic mouse; Disadvantaged; Distant; DNA Structure; dopaminergic neuron; Electromagnetic Fields; Endocrine; Energy Metabolism; Ensure; Epitopes; Exposure to; Feeding behaviors; ferrous oxide; Fiber Optics; Foundations; Frequencies (time pattern); Gene Expression; Gene Expression Regulation; Glucagon; Glucose; glucose metabolism; Glycocalyx; Goals; Gold; Heating; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Image; implantation; In Vitro; in vivo; Individual; induced pluripotent stem cell; Injection of therapeutic agent; Insulin; insulin secretion; Internal Ribosome Entry Site; Investigation; Ion Channel; iron oxide; Lead; Life; Light; Luciferases; Membrane; Membrane Potentials; Metals; Methodology; Methods; Mitochondria; Modeling; Monitor; mouse model; nanoparticle; Neurons; new technology; novel strategies; Nude Mice; Operative Surgical Procedures; Optical Methods; Organism; particle; patch clamp; Peripheral; Physiological; Physiological Processes; Physiology; Plasma; Play; Population; Process; Promotor (Genetics); Proteins; Protocols documentation; radiofrequency; relating to nervous system; Relative (related person); Reporter; research study; response; Response Elements; Rewards; Rhodopsin; Role; Safety; Slice; Staging; Streptavidin; Structure of nucleus infundibularis hypothalami; System; Techniques; Technology; Temperature; Testing; Time; tool; Transgenic Mice; TRPV1 gene; tumor
Relevance: This proposal aims to validate a novel technology, Nanoparticle Induced Circuit Excitation (NICE), for external, non-invasive activation of defined cell populations in living animals. We propose to apply this methodology to express insulin and thus control glucose in diabetic animals and to modulate feeding behavior by activating specific neural populations. The studies proposed in this application will thus validate the use of NICE and provide a foundation for the eventual use of nanoparticles in clinical settings
Project start date: 2011-09-26
Project end date: 2015-04-30
Budget start date: 26-SEP-2011
Budget end date: 30-APR-2012
PFA/PA: PA-08-052
1R01GM095654-01A1 (2011): $398884