PORTABLE MOTION COMPENSATED SDOCT SYSTEM FOR IMAGING YOUNG CHILDREN
A Joseph
Duke Universitycity: Durham country: United States (us)
Grant 1R21EY021321-01A1 from National Eye Institute
Abstract: Eye diseases of young children, if not detected and treated early, can lead to serious vision loss and even blindness. Currently, retinal diseases in young children are mainly recorded and monitored by color photographs, even though they provide limited information about ophthalmic disease processes and mechanisms. As an alternative to the classic 2-D color photographs, novel spectral domain optical coherence tomography (SDOCT) imaging systems can provide 3-D images of intra-retinal structures. In adults, tabletop SDOCT provides significantly more useful diagnostic information and is now a standard for the diagnosis and management of retinal diseases. Our preliminary studies based on handheld SDOCT (HH-SDOCT) snapshots of neonatal retina have already provided some unique and previously unseen information about disease progression in young children. However, due to the infant´s head/eye motion, it is extremely cumbersome to effectively image a complete 3-D tomographic view of the macula in young, awake children and accurately measure and quantify disease biomarkers. Our long-term goal is to improve the vision outcomes of at-risk young children with ocular diseases through earlier and better-directed therapy. To achieve this goal, we will take advantage of recent advances in image processing and optics as an integrated technology to capture 3-D retinal images with higher resolution and better motion stability compared to any previous imaging technique, which will ultimately provide quantitative measurements of novel imaging biomarkers of the onset and progression of young children´s ophthalmic diseases. We will achieve our objectives by pursuit of the following three specific aims Aim 1 Develop hardware to customize the handheld SDOCT and Doppler-SDOCT systems for retinal imaging of non- sedated young children. Aim 2 Develop software to control the hardware in Aim 1 and to automatically analyze the captured images for detecting imaging biomarkers of the onset and progression of retinal diseases in young children. Aim 3 Perform a pilot study in adults and young children. Evaluate, provide feedback, and improve the performance of methodologies in Aims 1&2, and then test the utility and validity of images and measurements compared to conventional diagnostic methods. The results of this study have the potential to provide practical diagnostic tools and methodologies that will revolutionize the management of pediatric ocular diseases. This contribution would be significant as the first step in a continuum of research leading to better-directed therapy of ocular diseases in young children based on accurate quantitative measurement of disease imaging biomarkers and accurate staging of foveal development. Eye diseases of young children, if not detected and treated early, can lead to serious vision loss and even blindness. We propose to develop a technology to adapt spectral domain optical coherence tomography imaging systems, currently widely used for imaging adults, as a novel and efficient ocular disease diagnostic tool in young, awake children
Keywords: 3-Dimensional; Adult; Age related macular degeneration; Animal Model; awake; base; Basic Science; biomarker; Blindness; Blood Vessels; Cardiovascular Diseases; Caring; Child; Childhood; Clinical Sciences; Color; Computer software; cost; cost effective; Development; diagnosis standard; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Eye; Eye diseases; Feedback; Goals; Hand; Head; Image; image processing; Imaging Device; Imaging Techniques; improved; Infant; innovation; Lead; macula; Measurement; Measures; Methodology; Monitor; Morphology; Motion; Neonatal; Neurologic; novel; Optical Coherence Tomography; Optics; Outcome; Pathologic Neovascularization; Performance; Pharmacotherapy; Pilot Projects; Population; Positioning Attribute; Process; Research; Research Personnel; Resolution; Retina; retina blood vessel structure; Retinal; Retinal Diseases; Retinopathy of Prematurity; Risk; Screening procedure; software development; Staging; Structure; System; Technology; Testing; Three-Dimensional Image; tool; Vision; young adult
Relevance: Eye diseases of young children, if not detected and treated early, can lead to serious vision loss and even blindness. We propose to develop a technology to adapt spectral domain optical coherence tomography imaging systems, currently widely used for imaging adults, as a novel and efficient ocular disease diagnostic tool in young, awake children
Project start date: 2012-01-01
Project end date: 2013-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
1R21EY021321-01A1 (2012): $221766
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Joseph
ANALYSIS OF INTERGENIC TRANSCRIPTION AND ITS ROLES IN YEAST GENE EXPRESSION
A Joseph, Assistant Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R01GM080470-05 from National Institute Of General Medical Sciences
Abstract: Transcription from non-protein-coding DNA (ncDNA), including intergenic DNA, is widespread among eukaryotes. However, the consequences of this transcription are only beginning to be investigated. The long-term objective for this project is to understand how transcription of ncDNA regulates gene expression. This grant focuses on our recent discovery of a previously uncharacterized mechanism of gene regulation repression by intergenic transcription. In Saccharomyces cerevisiae, we showed that expression of an intergenic transcript, SRG1, represses the transcription of the adjacent SER3 gene. However, we found that it is the act of transcription, not the SRG1 ncRNA product, which mediates repression by a transcription interference mechanism. In this proposal, we plan to extend these studies by using a combination of genetic, molecular, genomic and biochemical approaches. First, we will identify and characterize factors involved in both the activation and repression of SER3. The results of these studies will provide important insights into the mechanism of repression by intergenic transcription and establish tools to characterize the function of new cases of intergenic transcription. Second, we will begin to dissect the molecular details of this repression mechanism. Using both gene expression analysis and chromatin immunoprecipitation methods, we will determine the relationship between the rate of intergenic transcription and repression of the adjacent gene and test the hypothesis that intergenic transcription modifies chromatin structure to repress the adjacent gene. Third, we will identify and characterize new cases of repression by intergenic transcription. This will allow us to extend our analysis to more genes in order to understand the general features of this repression mechanism. We will focus our analysis on a subset of intergenic DNAs that represent strong candidates for repression by intergenic transcription based on results from our genome- wide RNA Pol II ChIP studies and more recent yeast whole-genome expression studies. It is becoming increasingly clear that transcription of ncDNA plays an important role in regulating normal cell growth and development in humans and thus is likely to be involved in the prevention of human diseases, including cancer. Given that factors and mechanisms of transcription regulation are largely conserved among eukaryotes, our analysis of repression by intergenic transcription in yeast may provide new insight into the roles of transcription of ncDNA in humans
Keywords: Arabidopsis; Bacteria; base; Binding (Molecular Function); Biochemical; cell growth; chromatin immunoprecipitation; Chromatin Structure; Code; DNA; Dosage Compensation (Genetics); Drosophila genus; Eukaryota; Exons; Functional RNA; Fungal Genome; Gene Expression; Gene Expression Regulation; gene repression; Genes; Genetic; Genetic Transcription; Genome; genome wide association study; genome-wide; genome-wide analysis; Genomics; Goals; Grant; Growth and Development function; histone modification; Human; human disease; insight; Intergenic DNA; Intergenic Sequence; Introns; Malignant Neoplasms; Mediating; Methods; Microarray Analysis; MicroRNAs; Modeling; Molecular; Molecular Genetics; Mus; Normal Cell; novel; Nucleosomes; Organism; Physiological; Play; Positioning Attribute; Prevention; Prokaryotic Cells; Promotor (Genetics); Proteins; Regulation; Repression; Research; research study; RNA; RNA Polymerase II; Role; Saccharomyces cerevisiae; Small RNA; Surveys; Testing; tool; Transcript; Transcriptional Regulation; X Inactivation; Yeasts
Project start date: 2007-07-12
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5R01GM080470-05 (2011): $207822
DEVELOPMENT OF TAILORED INTERVENTION TO PROMOTE CRC SCREENING AMONG LATINO MEN
A Joseph, Associate Professor Of Medicine
Memorial Hospital Of Rhode Islandcity: Pawtucket country: United States (us)
Grant 1R21CA152833-01A1 from National Cancer Institute
Abstract: This application is in response to the Program Announcement "Health Promotion among Racial and Ethnic Minority Males" (PA-07-421). Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality among Latinos despite effective screening methods. While rates of screening overall have increased, the disparities in CRC screening between non-Latino Whites and Latinos have also increased. Even after accounting for socioeconomic factors, screening rates are lower for Latinos than for non-Latino Whites suggesting that there are other factors and barriers to CRC screening that are specific to Latinos. A conceptual framework known as "positive deviance" is a particularly promising approach for addressing barriers to CRC screening among Latinos. The central premise behind positive deviance is that solutions to common problems found in a community often already exist in that community but they go unrecognized and so are underutilized. A positive deviance approach identifies behaviors associated with success and disseminates strategies for adopting these behaviors to others. When applied to CRC screening, this approach can identify specific barriers to screening as well as strategies to overcome these barriers. Video is an ideal medium for disseminating the strategies that "positive deviants" or "successful peers" use to overcome barriers to CRC screening. A positive deviance approach combined with video can thus capitalize on the screening behaviors of "successful peers" in a community and make behavioral interventions particularly relevant and culturally appropriate to others in that community. The purpose of this proposal is to explore barriers to CRC screening encountered by Spanish-speaking Latino men, identify successful strategies used by successful peers to overcome barriers and in so doing, use a positive deviance approach to develop a culturally and linguistically appropriate tailored video-based intervention to increase CRC screening among Spanish-speaking Latino men. Colorectal cancer screening rates are low, especially among Latinos with limited English proficiency. "Positive deviants" or "successful peers" are those individuals in a community who practice a healthy behavior (e.g. colorectal cancer screening) when the majority do not. This project will use a "positive deviance" approach to create a culturally and linguistically appropriate innovative personalized video intervention to promote colorectal cancer screening among Spanish-speaking Latino men
Keywords: Accounting; Address; Adopted; Area; Attitude; base; Behavior; Behavior Therapy; Cancer Etiology; Childhood; Colorectal Cancer; colorectal cancer screening; Communities; Contraceptive methods; Databases; Decision Making; design; Development; deviant; digital; Educational aspects; Evaluation; experience; Goals; Health; Health Promotion; improved; Individual; innovation; Intention; Intervention; Interview; Latino; male; men; Methods; Minority Groups; Morbidity - disease rate; Mortality Vital Statistics; NIH Program Announcements; nutrition; Participant; peer; Primary Health Care; Process; public health medicine (field); public health relevance; Recruitment Activity; response; Safe Sex; Screening procedure; skills; Socioeconomic Factors; Solutions; success; Testing; Underserved Population; Video Recording; Vulnerable Populations
Project start date: 2011-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-421
1R21CA152833-01A1 (2011): $176584
TRAINING IN CARDIOVASCULAR RESEARCH
A Joseph, Professor & Chief
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5T32HL007360-34 from National Heart, Lung, And Blood Institute
Abstract: The purpose of this training program is to select talented and committed young investigators and to prepare them for careers in cardiovascular research. This program has been in place at this institution since 1978. A substantial number of our previous trainees remain active in research and have made notable contributions to cardiovascular investigation. We are proud of this tradition, and the current proposal preserves many features of our previously successful program. The only important organizational change since the last competitive renewal in 1997 is the replacement of the Program Director, R. Sanders Williams, M.D., by L. David Hillis, M.D. The 3 Associate Directors (Drs. Eric Olson, Masashi Yanagisawa, and James Stull) remain in place, as do many of the Participating Faculty. We request funds for 8 predoctoral and 16 postdoctoral positions annually (unchanged from previously). Our faculty is multidisciplinary 55 individuals who represent 10 academic departments and 8 Graduate School programs. The faculty are linked by a common interest in important problems of cardiovascular biology and medicine as well as by an interlocking network of collaborative activities, including several research centers and PPG grants. Cardiovascular research training is offered in 4 general areas (1) Developmental and Molecular Biology, (2) Vascular Biology, (3) Physiology and Signaling, and (4) Clinical Sciences. This Program gives particular attention to (a) the integration of molecular genetics and biological chemistry with physiological investigations in a broad range of model organisms and human subjects, (b) to issues of scientific integrity and ethics, and (c) to increasing the participation of females and underrepresented minority groups in the training program, both as participants and as faculty
Keywords: Cardiovascular system; Research; Training
Project start date: 1978-07-01
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-06-468
5T32HL007360-34 (2011): $617940
MASS SPECTROMETRY OF PROTEIN ASSEMBLIES
A Joseph, Professor
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5R01RR020004-08 from National Center For Research Resources
Abstract: The overall goal of our project is to develop advanced technologies based on electrospray ionization with mass spectrometry (MS) and ion mobility spectrometry (IMS) for proteomics and structural biology. The structural determination of protein complexes can play an important role in the fundamental understanding of biochemical pathways. New techniques will be developed to facilitate the characterization of noncovalent protein assemblies. Information related to protein size, protein folding, and protein conformation that can be used to complement information derived from more traditional high resolution structural methods (e.g., x-ray crystallography, nuclear magnetic resonance, cryoelectron microscopy) will be derived from study of the gas phase protein complexes. Modifications to ion mobility spectrometry systems will allow temperature dependences of the ions traveling in the IMS to be used to follow protein folding/unfolding. Experimental and instrumental methods to reduce the charge states of the gas phase complexes, such as gas phase proton transfer reactions, will be developed; cross-sections from their mobility profiles will be determined to study the structural affects of assembly and ligand binding (i.e., conformational differences). Novel developments in intact protein tandem MS will be exploited to define the sites of ligand and protein interactions in a given noncovalent protein complex. Top-down MS/MS will be developed further as a means to determine the specific sites of small molecule ligand binding. The ability to increase the multiple charging of large noncovalent gas phase molecules will be implemented to increase the efficiency of the top-down MS analysis of protein-ligand complexes. The developed methods will be used to determine the binding sites of metals to metalloproteins involved in neurodegenerative disorders and ATP to protein kinases. MS/MS will be used to deliver a "signature" for ATP-binding that can be used to identify new protein kinases. ESI-MS and MS/MS of protein-ligand binding from structurally diverse compound libraries will be developed as a complementary tool for fragment-based ligand design strategies. We aim to develop more robust analytical technologies that can be applied to provide structural information for biologically important proteins, such as proteins involved in neurodegenerative disorders (e.g., Alzheimer´s disease, Parkinson´s disease). New methodologies to determine to sites of drug binding to targeted proteins will be developed
Keywords: Address; Affect; Alzheimer`s Disease; Amino Acids; Architecture; base; Binding (Molecular Function); Binding Proteins; Binding Sites; Biochemical Pathway; Cell physiology; Cells; Charge; Complement; Complex; Coupled; Cryoelectron Microscopy; Crystallography; Dependence; design; Development; Devices; Dissociation; Drug Binding Site; Electrons; Electrospray Ionization; Fruit; Gases; Genome; Goals; Health; Heterogeneity; Human Genome; Hybrids; improved; instrument; ion mobility; Ions; Libraries; Ligand Binding; Ligands; mass spectrometer; Mass Spectrum Analysis; Measures; Metal Binding Site; Metalloproteins; Methodology; Methods; microchip; Modification; Molecular; Molecular Analysis; molecular mass; Multi-Drug Resistance; Neurodegenerative Disorders; novel; Nuclear Magnetic Resonance; Organism; Parkinson Disease; particle; Phase; Play; Process; programs; Protein Analysis; protein complex; Protein Conformation; protein folding; Protein Kinase; Proteins; Proteomics; Protons; public health medicine (field); Reaction; Research; Resolution; Ribonucleoproteins; Role; Site; small molecule; Solutions; Spectrometry; Spectrometry, Mass, Electrospray Ionization; structural biology; structural genomics; Structure; System; tandem mass spectrometry; Techniques; Technology; Temperature; Time; tool; Travel
Relevance: Relevance to Public Health We aim to develop more robust analytical technologies that can be applied to provide structural information for biologically important proteins, such as proteins involved in neurodegenerative disorders (e.g., Alzheimer´s disease, Parkinson´s disease). New methodologies to determine to sites of drug binding to targeted proteins will be developed
Project start date: 2004-07-15
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01RR020004-08 (2011): $374428
STUDIES ON THE REGULATION OF OSTEOCLAST PRECURSOR CELLS
A Joseph, Professor/clinical
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)
Grant 5R01AR048714-08 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The goal of these studies is to understand the effects that the systemic regulatory factor, parathyroid hormone (PTH), has on the migration and homing to bone of circulating osteoclast precursor cells. Rationale Osteoclasts are unique cells that resorb bone and are coregulators (with osteoblasts) of bone turnover, bone mass and bone quality. However, we have only limited knowledge of what steps are involved in their maturation. Specifically, this application will focus on the question of what path osteoclast precursors take to migrate to bone. Currently, it is unknown whether osteoclast precursor cells, which originate in bone marrow, 1) migrate directly from bone marrow to adjacent bone, where they mature and function as resorbing cells or if they 2) first migrate from the bone marrow to the circulation, undergo a maturation step extramedullary and then return to bone to become resorbing cells. It is also unclear whether systemic regulators of bone homeostasis like PTH alter the bone marrow microenvironment and increase the circulation and homing of osteoclast precursors to bone. It is also possible that both pathways are important and that endosteal and trabecular bone remodeling at sites adjacent to bone marrow are regulated by the pathway 1, while periosteal resorption and osteoclast formation at sites not adjacent to bone marrow are dependent on pathway 2. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases. Specific Aim 1 Define the population of osteoclast precursor cells in the bone marrow and periphery (blood and spleen) and determine if parathyroid hormone (PTH) treatment in vivo alters their relative proportions or absolute number in mice. Specific Aim 2 Determine if osteoclast precursor cells migrate extramedullarily and then home to bone in the basal state or after treatment of mice with parathyroid hormone. These studies will examine the relevance of extramedullary circulation in the maturation of osteoclasts, which are the only cells capable of efficiently resorbing bone. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases
Keywords: Aftercare; Animals; Area; Blood; Blood Circulation; bone; bone loss; Bone Marrow; bone mass; bone quality; Bone remodeling; bone turnover; Cell surface; Cells; Development; Extramedullary; Goals; Health; Home environment; Homeostasis; Homing; human PTH protein; improved; in vivo; Intervention; Knowledge; Mature Bone; Metabolic Bone Diseases; migration; Morbidity - disease rate; Mus; Myeloid Cells; Osteoblasts; Osteoclasts; Osteoporosis; Parathyroid Hormones; Pathologic; Pathway interactions; Pattern; Peripheral; Phenotype; Physiology; Population; precursor cell; prevent; Regulation; Relative (related person); Role; Site; Spleen; substantia spongiosa; Tissues
Project start date: 2002-08-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01AR048714-08 (2011): $290110
NEW APPROACHES TO ASSESS AND FORESTALL OSTEOARTHRITIS IN INJURED JOINTS
A Joseph
University Of Iowacity: Iowa City country: United States (us)
Grant 5P50AR055533-05 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The goal of the University of Iowa CORT is to develop new methods of forestalling post-traumatic osteoarthritis (PTOA) through a multi-disciplinary translational approach including basic science, bioengineering, imaging, and clinical research. The central theme is that joint injuries initiate a sequence of biologic events that lead to PTOA and that new treatments of joint injuries will minimize these deleterious events and promote joint healing. The specific aims are to 1) advance understanding of the pathogenesis of PTOA, 2) develop and refine reliable quantitative measures of severity of joint injuries, including measures of structural damage and biologic response to joint injury, and 3) apply the advances in understanding of the pathogenesis of PTOA and assessment of joint injury to new methods of forestalling PTOA. The four CORT projects are 1. Cartilage Extracellular Matrix Fragments and Trauma-Induced Chondrolysis, an in vitro study that will identify pathways responsible for propagation of cell damage following injury; 2. Acute versus Chronic Mechanical Damage in the Etiology of PTOA, an experimental study that will define the role of loading of injured joints in causing OA, and new methods for preventing OA in injured joints; 3. Validation and Application of MRI Biomarkers in Assessing Articular Cartilage Health, a clinical and experimental study of non-fracture cartilage injury that will help define the ability of non-invasive measures to assess the severity of cartilage damage, that will identify which synovial fluid markers of acute joint injury reflect that damage, and that will test the hypothesis that decreased loading accelerates restoration of injured joint surfaces; and 4. Quantifying Injury Severity to Assess the Risk for Post-Traumatic OA, a clinical study of intra-articular fractures that will examine the hypothesis that new quantitative measures of the severity of structural joint injury predict clinical outcomes. This project also will conduct a multi-center study of the severity of joint injury, in preparation for clinical trials of molecular interventions to minimize the risk of OA following joint injury. The four projects will be supported by an administrative-biostatistics core, a biomechanics-imaging core, and a tissue and experimental modeling core
Relevance: Osteoarthritis (OA) is the most common joint disease and is among the most important causes of pain, disability, and economic loss. About 12% of OA arises following joint trauma. The risk of OA ranges from 20% to 50% or more following many common joint injuries; and, despite evolving surgical methods of treating joint injuries, this risk has not decreased appreciably in the last 20 years. The basic science, bioengineering and clinical research in this CORT will lead to new biologic and improved minimally invasive operative treatments of joint injury that will forestall OA and thereby improve the lives of hundreds of thousands of people
Project start date: 2007-09-10
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-AR-06-003
5P50AR055533-05 (2011): $1355457
AWARENESS ENHANCEMENT AND MONITORING DEVICE FOR TREATMENT OF TRICHOTILLOMANIA
A Joseph
Hammzoco Technologiescity: Ann Arbor country: United States (us)
Grant 5R42MH077362-03 from National Institute Of Mental Health
Abstract: The goal of the proposed research is to further refine and evaluate an inconspicuous, awareness- enhancement and monitoring device (AEMD) which will assist the treatment of trichotillomania (TTM). TTM is associated with significant impairments in social functioning and often has a profound negative impact on self- esteem and well being. Conservative estimates suggest that 0.6% percent of the US population, or about 1.8 million people, meet full diagnostic criteria for TTM and approximately 7.5 million US residents have significant hair pulling problems. Of those treated, 60% to 70% are wholly or partially refractory to standard behavioral and pharmacological treatments and could therefore potentially benefit from this device. Best practice treatment for TTM involves a form of behavioral therapy known as habit reversal therapy (HRT). HRT requires persons with TTM to be aware of their hair pulling behaviors, yet the majority of persons with TTM pull most of their hair outside of their awareness. HRT also requires TTM sufferers to record the frequency and duration of their hair pulling behaviors yet it is impossible for a person to monitor behaviors that they are unaware of. Our Phase I efforts have produced a prototype device (AEMD) that solves these two problems. The prototype AEMD signals the TTM sufferer if their hand approaches their hair, thereby bringing pulling-related behavior into awareness. The prototype AEMD also logs the time, date, duration, and user classification of hair pulling related events. Our published pilot study and subsequent investigations establish that the prototype AEMD successfully alerts TTM sufferers to pulling-related behaviors and monitors TTM-related behavior in a laboratory setting. With respect to technological innovation, this project has the potential to develop the first available miniaturized, wearable, patient interactive, real-time data collecting and proximity-sensing device that both alerts sufferers to the presence of mental illness symptoms as they occur and keeps track of the frequency and intensity of the problem. The patented technologies developed for the AEMD have the potential to be of great value for a range of other health/mental health conditions or industrial applications. Our overall Phase II aim is to further refine the AEMD and to evaluate its acceptance and utility when used in an open trial course of professionally-led habit reversal therapy. It is hypothesized that the AEMD will be enthusiastically accepted by TTM sufferers and their clinicians and that it will perform as designed during the clinical trial. The Phase II AEMD will include a bracelet(s)/watch to be worn on each wrist, another element to be placed at the rear base of the neck, and a pager-like alert device to be worn at the belt-line or in a pocket. The AEMD, if found to be useful and effective, has the potential to significantly reduce the symptoms of TTM and its associated functional impairments. The AEMD also has great potential to improve assessment and monitoring of TTM behaviors which could be invaluable to clinicians planning treatment and to researchers evaluating the efficacy of various treatment strategies. This Phase II project involves continued design, development and evaluation of a device that aids in the treatment of trichotillomania. The device enhanced awareness of pulling behavior and monitors this disabling condition
Keywords: Awareness; base; Behavior; Behavior monitoring; Behavior Therapy; Benign; Classification; Clinic; Clinical; Clinical Trials; Code; Computer Analysis; Coughing; Data; Data Collection; design; Development; Device Designs; Devices; Diagnosis; Diagnostic; Disease; efficacy trial; Electromagnetic Fields; Elements; Evaluation; Event; falls; Frequencies (time pattern); functional disability; Future; Goals; Government; Habits; Hair; Hand; Head; Head Movements; Health; Home environment; Hour; Impairment; impression; improved; Investigation; Laboratories; Legal patent; Life; magnetic field; meetings; Mental disorders; Mental Health; Miniaturization; miniaturize; Monitor; monitoring device; Neck; Patients; Pattern; Personal Computers; Persons; Pharmacological Treatment; Phase; Pilot Projects; Population; prototype; public health relevance; Publishing; Randomized Controlled Trials; Recurrence; Refractory; Research; Research Personnel; self esteem; sensor; Signal Transduction; Social Functioning; success; Symptoms; System; technological innovation; Technology; Testing; Time; toothbrush; Toothbrushing; Touch sensation; treatment effect; treatment planning; treatment strategy; Trichotillomania; Wrist
Relevance: This Phase II project involves continued design, development and evaluation of a device that aids in the treatment of trichotillomania. The device enhanced awareness of pulling behavior and monitors this disabling condition
Project start date: 2006-04-01
Project end date: 2012-12-31
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-09-081
5R42MH077362-03 (2011): $411276
METABOLISM AND FUNCTION OF CYCLIC NUCLEOTIDES
A Joseph
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R01DK021723-30 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The amplitude and duration of the signals conveyed by the cyclic nucleotide second messengers, camp and cGMP, are controlled by their relative rates of synthesis and degradation. For many years now our laboratory has worked to understand the regulation of cyclic nucleotide degradation by phosphodiesterases (PDEs). Each animal species produce many different PDEs. To date 11 different PDE gene families have been identified most of which contain multiple genes each of which produce several different isozymes by the processes of alternative splicing of mRNA. We and others have made good progress in determining the physiological functions for some of these variant isozymes. It is the hypothesis of this proposal that many more PDE mRNA/isozyme variants remain to be identified and that until we do so, we cannot really understand the details of cyclic nucleotide mediated regulation of physiological processes. We propose an approach involving, bioinformatic searches, gene array identification, and standard methods of molecular biology and enzymology to identify, verify, clone, express, and characterize these new PDEs. We also propose to continue to determine functions for individual PDEs by characterizing the phenotypes of animals (and cells derived from these animals) that have specific disruptions of the genes encoding a particular PDE isozyme. As part of this second approach we propose to utilize a new methodology that is expected to allow conditional, reversible, tissue specific ablation of individual PDE expression. The methods make use of specific antisense and siRNA expression under the graded control of drug inducible promoters
Keywords: Ablation; Alternative Splicing; Animal Model; Animals; Bioinformatics; Camping; Cell Line; cell type; Cells; Condition; Cultured Cells; Cyclic GMP; Cyclic Nucleotides; Data; Development; Disruption; Drug Controls; Enzymatic Biochemistry; Enzymes; Exons; Family member; Gene Family; Genes; genome database; Hand; Hormonal; Individual; Isoenzymes; Knowledge; Laboratories; Mediating; Messenger RNA; Metabolism; Methodology; Methods; Molecular Biology; Numbers; Oligonucleotides; Pattern; Pharmaceutical Preparations; Phenotype; phosphoric diester hydrolase; Physiological; Physiological Processes; Process; programs; Promotor (Genetics); Property; Rate; Regulation; Relative (related person); Research Personnel; RNA Splicing; Role; Role playing therapy; second messenger; Second Messenger Systems; Signal Transduction; Small Interfering RNA; Standards of Weights and Measures; Time; Tissues; Transgenic Animals; Variant; Work
Project start date: 1978-09-15
Project end date: 2009-07-31
Budget start date: 1-AUG-2007
Budget end date: 31-JUL-2009
5R01DK021723-30 (2007): $335719
5R01DK021723-29 (2006): $345899
REGULATION OF THE PHYSIOLOGIC AND PATHOLOGIC ACTIVATION OF THE NLRP3-INFLAMMASOME
A Joseph, Assistant Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5R01AI088255-02 from National Institute Of Allergy And Infectious Diseases
Abstract: The ability to recognize pathogens and initiate inflammatory and immunologic processes to control their spread relies on innate immune system signaling. One of the most recently identified pathogen-sensing signaling pathways involves the activation of the inflammasome, a macromolecular complex responsible for proteolytic processing of several immature cytokines (IL- 12 and IL-18 in particular). The ATP-binding protein NLRP3 acts as a central scaffold during in the assembly of the inflammasome. In addition to cytokine processing, we have recently found that signaling through NLRP3 activates a novel cell death program with morphologic and biochemical features of necrosis. The NLRP3-inflammasome can be activated by numerous stimuli known to induce IL-12 secretion, suggesting that the physiologic role of NLRP3 is to integrate the response to a range of pro-inflammatory triggers. Mutations in the nucleotide-binding domain of NLRP3 can cause inherited periodic fever syndromes. We have also recently discovered that some critical virulence factors from Staphylococcus aureus activate the NLRP3 inflammasome as well. S. aureus that express these virulence factors can cause with severe necrotizing pneumonias that are characterized by systemic inflammatory response and tissue necrosis. We believe activation of NLRP3 by mutation and pathogen-dervived virulence factors represent pathologic events that lead to dysregulated inflammation and progression diseases associated with these stimuli. We now propose to further investigate both the molecular mechanisms regulating NLRP3 activation and its role in the pathogenesis of S. aureus infections. These studies will provide crucial information in understanding inflammatory signaling processes involved in the pathogenesis of a huge array of human diseases. We have found that several virulence factors from Methicillin Resistant S. aureus (MRSA) activate an innate immune signaling complex known as the inflammasome. We propose to carry out studies to understand how activation of host inflammation by the inflammasome affects the pathogenesis of MRSA infections. We also propose detailed studies into the mechanism that underlies activation of the inflammasome, which may identify targets for the development of pharmacologic agents that could improve the treatment of these deadly infections
Keywords: Affect; Antibiotics; Apoptosis; Apoptotic; ATP Hydrolysis; ATP phosphohydrolase; Binding (Molecular Function); Binding Proteins; Biochemical; Caspase-1; Cathepsins B; Cell-Free System; Cells; Complex; computerized data processing; Cultured Cells; Cysteine Protease; cytokine; Development; Disease Progression; Event; Fever; G-substrate; Gene Components; Genes; GTP-Binding Proteins; guanine nucleotide binding protein; Hemolysin; Human; human disease; Immune; Immune response; Immune system; Immunologics; improved; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; inhibitor/antagonist; Injury; Interleukin-12; Interleukin-18; knock-down; Lead; Life; lung injury; Macromolecular Complexes; Mediating; methicillin resistant Staphylococcus aureus (organism); Molecular; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Mutation; Necrosis; novel; Nucleotides; Panton-Valentine leukocidin; pathogen; Pathogenesis; Pathologic; Peptide Hydrolases; Physiological; Pneumonia; prevent; Process; Proteins; Proteolytic Processing; public health relevance; Recombinants; reconstitution; Regulation; response; Role; scaffold; Signal Pathway; Signal Transduction; small hairpin RNA; Staphylococcus aureus; Stimulus; Syndrome; System; Tissues; Toxin; Virulence Factors
Project start date: 2010-05-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01AI088255-02 (2011): $333000
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR MECHANISMS DICTATING SIRT1/HIF-2 SIGNALING DURING HYPOXIA
A Joseph, Assistant Professor
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 1R01HL108104-01A1 from National Heart, Lung, And Blood Institute
Abstract: The ability to recognize and respond to environmental stress is an essential characteristic of all living organisms. A low oxygen state, or hypoxia, is an environmental stress encountered under physiological as well as pathophysiological disease states such as myocardial infarction and stroke. In higher eukaryotes, the cell-intrinsic transcriptional hypoxia response includes actions mediated by Hypoxia Inducible Factor (HIF) transcription factors. In vertebrates, the HIF family is comprised of three members with HIF-1 and HIF-2 being essential for survival as indicated by results from genetic ablation studies in mice. Despite their similarity at the protein level, HIF-1 and HIF-2 have distinct biological roles. HIF-2 is the specific HIF factor responsible for induction of erythropoietin and of major antioxidant enzymes (AOE) in adult mice, thereby regulating cell survival and protective cellular responses against oxidative stress, respectively. We recently demonstrated that HIF-2, but not HIF-1, signaling during hypoxia is selectively augmented by Sirtuin 1 (Sirt1), a deacetylase also implicated in aging, nutrient sensing, and genotoxic stress response. Our central hypothesis is that Sirt1/HIF-2 signaling is an essential signaling pathway for protection against hypoxia-induced damage in mammals. Preliminary data within this proposal reveal that Sirt1 levels increase during hypoxia, HIF-2 is acetylated by specific cellular acetyltransferases during hypoxia, and cardiomyocyte-specific HIF-2 ablation in mice results in worse outcome following myocardial infarction. The experiments proposed are aimed at elucidating the mechanism and biological role for Sirt1/HIF-2 signaling in mammals using test tube, cell culture, and animal model studies. Our long-term goals are to identify the prosurvival mechanisms activated during hypoxia and to leverage this knowledge to develop novel therapeutic agents for treatment of myocardial infarction and stroke, the leading causes of morbidity and mortality in US adults today. The Specific Aims of this proposal are as follows Aim 1 Define the role of HIF signaling in Sirt1 activation during hypoxia Aim 2 Define the role of acetylation in Sirt1/HIF-2 signaling Aim 3 Define the role of HIF-2 in cardiac physiology after myocardial infarction A low oxygen level is a major feature of several human diseases including heart attack, stroke, and cancer. When faced with this stress, cells in our body respond by turning on genes in an attempt to survive. Understanding how this response is controlled will allow us to design new drugs that will save cells (as desired after a heart attack or stroke) or to kill cells (as desired in the case of cancer)
Keywords: Ablation; Acetylation; Acetyltransferase; Acute; Adult; Affect; Aging; Animal Model; Antioxidants; base; bHLH-PAS factor HLF; Biological; biological adaptation to stress; Biology; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cell Death; cell killing; Cell Survival; Cells; Cellular Stress; Characteristics; Complex; Data; Deacetylase; design; detection of nutrient; disability; Disease; Enzymes; EP300 gene; Erythropoietin; Eukaryota; Exposure to; Family; Feedback; Gene Expression; Genes; Genetic; Genotoxic Stress; Goals; Heart; human disease; Hypoxia; Hypoxia Inducible Factor; hypoxia inducible factor 1; Ischemia; Knowledge; Life; Link; Malignant Neoplasms; Mammals; Mediating; member; Messenger RNA; Molecular; Morbidity - disease rate; Mortality Vital Statistics; Mus; Myocardial Infarction; Myocardium; NADH; Nature; novel; novel therapeutics; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pharmaceutical Preparations; Physiological; Physiology; Play; preconditioning; Proteins; Regulation; research study; response; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; stroke; Testing; Therapeutic Agents; Tissues; transcription factor; Tube; United States; Vertebrates
Relevance: A low oxygen level is a major feature of several human diseases including heart attack, stroke, and cancer. When faced with this stress, cells in our body respond by turning on genes in an attempt to survive. Understanding how this response is controlled will allow us to design new drugs that will save cells (as desired after a heart attack or stroke) or to kill cells (as desired in the case of cancer)
Project start date: 2011-07-15
Project end date: 2015-05-31
Budget start date: 15-JUL-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
1R01HL108104-01A1 (2011): $302000
TADALAFIL INDUCED MODULATION OF IMMUNE RESPONSE IN HNSCC
A Joseph, Assoc Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R21CA135635-02 from National Cancer Institute
Abstract: Tadalafil induced modulation of immune response in HNSCC Head and neck squamous cell carcinoma (HNSCC) affects over 40,000 individuals per year in the United States, however cure rates for advanced disease hover around 50%. HNSCC patients demonstrate significant impairment in immune recognition of tumor cells, and evasion from immune response is a significant factor in HNSCC carcinogenesis. Preliminary data from our laboratory suggest that mature CD11b+/GR1+ myeloid derived suppressor cells (MDSC)s induce a suppressive phenotype resulting in tumor-specific T cell anergy in both CD4+ and CD8+ T-cells in HNSCC, and that functional elimination of MDSCs via phosphodiesterase 5 (PDE5) inhibitors can restore T cell function in lymphocytes from HNSCC patients. This study will examine the candidacy of tadalafil as an immunotherapeutic agent to reverse MDSC mediated suppression of T cell function in patients with HNSCC. Head and neck squamous cell carcinoma (HNSCC)is associated with cure rate of approximately 50% and evasion from immune response is a significant factor in HNSCC carcinogenesis. This study will examine the candidacy of tadalafil as an immunotherapeutic agent to reverse suppression of T cell function in patients with HNSCC
Keywords: advanced disease; Affect; After Care; After-Treatment; Aftercare; Apoptosis; Apoptosis Pathway; arginase; arginine amidinase; Assay; base; Bioassay; Biologic Assays; Biological Assay; biological signal transduction; Biopsy; canavanase; Cancer Genes; Cancer Induction; Cancer-Promoting Gene; Candida; carcinogenesis; Carcinoma, Epidermoid; Carcinoma, Planocellular; Carcinoma, Squamous; CD11b; CD4 lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cell Communication and Signaling; Cell Count; Cell Death, Programmed; Cell Function; cell mediated hypersensitivity; Cell Number; Cell physiology; Cell Process; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cells; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Chromosomal Instability; Chromosome Instability; Chronic; Cialis; clostridial tetanus; CR3A; Data; Delayed Hypersensitivity; Delayed-Type Hypersensitivity; delayed-type hypersensitivity response; EC 1.14.13.39; EDRF Synthase; Elements; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Growth Factor Synthase; Endothelium-Derived Relaxing Factor; Environment; Event; gain of function; Genes; Genetic; Guanylyl Cyclase-Activating Factor Synthase; Head and Neck; Head and Neck Carcinoma; Head and Neck Squamous Cell Carcinoma; Head and neck structure; helper T cell; Hepatic Proliferation Inhibitor; Histologic; Histologically; HNSCC; host response; IHC; Immune; immune function; Immune Function, Cellular; Immune response; Immunity; Immunohistochemistry; Immunohistochemistry Staining Method; immunologic preparation; immunoresponse; Immunosuppressants; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); immunosuppressive; Immunosuppressive Agents; Immunosuppressive Effect; Immunotherapeutic agent; immunotherapeutics; Impairment; indexing; Individual; Infiltration; Inflammatory Response; inhibitor; inhibitor/antagonist; Intracellular Communication and Signaling; ITGAM; ITGAM gene; L arginine amidinohydrolase; L-Arginine, NADPH[{..}]oxygen oxidoreductase (nitric-oxide-forming); Laboratories; Lilly brand of tadalafil; Liver Immunoregulatory Protein; Liver-Derived Inhibitory Protein; lymph cell; Lymphocyte; Lymphocytic; LYT3; MAC-1; MAC1A; magnetic beads; Malignant; Malignant - descriptor; Measures; Mediating; MO1A; Modality; Molecular; Monilia; Mononitrogen Monoxide; Myelogenous; Myeloid; NADPH-Diaphorase; Natural immunosuppression; neoplastic cell; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide, Endothelium-Derived; Nitric-Oxide Synthetase; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; NO Synthase; Oncogenes; pathway; Pathway interactions; Patients; PDE 5 enzyme; Peripheral; Phenotype; phosphodiesterase V; phosphodiesterase-5; Population; Process; Production; public health relevance; randomisation; randomization; Randomized; randomly assigned; Reaction; Regulatory T-Lymphocyte; response; Sampling; SCCHN; Series; Signal Transduction; Signal Transduction Systems; Signaling; Squamous cell carcinoma; Squamous Cell Epithelioma; Subcellular Process; Suppressor Cells; suppressor T lymphocyte; Suppressor-Effector T-Lymphocytes; T cell anergy; T Suppressor Cell; T-Cell Activation; T-Cells; T-Cells, Suppressor-Effector; T-Lymphocyte; T-Lymphocytes, Suppressor-Effector; T4 Cells; T4 Lymphocytes; tadalafil; Tetanus; therapeutic efficacy; therapeutically effective; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Transforming Genes; Treatment Efficacy; Tuberculin-Type Hypersensitivity; tumor; Tumor Burden; Tumor Cell; Tumor Load; tumor suppressor; Tumor Suppressor Proteins; Tumor-Derived; Type IV Hypersensitivity; United States
Relevance: Head and neck squamous cell carcinoma (HNSCC)is associated with cure rate of approximately 50% and evasion from immune response is a significant factor in HNSCC carcinogenesis. This study will examine the candidacy of tadalafil as an immunotherapeutic agent to reverse suppression of T cell function in patients with HNSCC
Project start date: 2009-01-01
Project end date: 2011-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2011
PFA/PA: PAR-08-025
5R21CA135635-02 (2010): $360800
CBT +/- MODAFINIL FOR INSOMNIA AND FATIGUE FOLLOWING CHEMOTHERAPY
A Joseph, Research Associate Professor
University Of Rochestercity: Rochester country: United States (us)
Grant 5R01CA126968-04 from National Cancer Institute
Abstract: Sleep disturbance, particularly insomnia, is far more prevalent in cancer survivors than in the general population. Insomnia is thought to occur in 40 percent to 65 percent of patients following anti-cancer treatment. Apart from its ubiquity, insomnia is strongly associated with fatigue and reduced quality of life (QOL) and is thought to be an important contributing factor to both. To date, very few studies have been conducted to determine if established methods used to treat insomnia in the general population, e.g., cognitive behavioral therapy for insomnia (CBT-I), are also effective in treating the insomnia that occurs with cancer and/or its treatment. New treatment strategies for this problem in cancer survivors are also needed, particularly ones that address the persistent fatigue that occurs in this patient group. A prime candidate for such research is modafinil. Preliminary data from our group show that modafinil reduces sleep problems and fatigue in breast cancer patients post treatment. We have also completed a study showing that modafinil enhances treatment compliance with CBT-I in patients with primary insomnia. These two initial studies, coupled with a recently published, very successful, randomized, controlled trial of CBT-I in breast cancer survivors, suggest a role for both CBT-I and modafinil in treating insomnia in cancer survivors. Accordingly, we propose that the combination of therapies will be particularly efficacious in cancer patients because the combined approach will allow for the management of the often interrelated symptoms of insomnia and fatigue in cancer survivors. Methods 226 Breast cancer survivors with chronic insomnia will be recruited and randomized to one of four treatment conditions (CBT-I, modafinil, both, or neither). The seven-week intervention is designed to determine the efficacy and acceptability of these treatment strategies in reducing insomnia and fatigue and in improving QOL in cancer survivors. Assessments will be made by diary and by questionnaires before, during, two weeks following, and three months following the study intervention. In addition, pre- and post-intervention polysomnographic assessments will be conducted in 100 of the 226 patients in order to characterize the effects of these interventions on sleep architecture
Keywords: 1, 2, 4-Triazolo(4, 3-a)pyridin-3(2H)-one, 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-; 2H-1, 4-Benzodiazepin-2-one, 7-chloro-1, 3-dihydro-3-hydroxy-1-methyl-5-phenyl-; 3-Hydroxydiazepam; acronyms; Address; Adverse effects; Affect; After Care; After-Treatment; Aftercare; Agonist; anticancer therapy; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Anxiety; Apnea, Sleep; arm; Beds; Behavior Therapy, Cognitive; Behavioral Therapy; benzhydrylsulfinylacetamide; Benzodiazepine Compounds; Benzodiazepine Receptor; Benzodiazepines; Cancer Center; cancer diagnosis; Cancer of Breast; Cancer Patient; Cancer Radiotherapy; Cancer Survivor; cancer therapy; Cancer Treatment; Cancers; CCOP; Cephalon brand of modafinil; chemotherapy; Chronic Insomnia; Clinical; cognitive behavior intervention; cognitive behavior modification; cognitive behavioral intervention; cognitive behavioral modification; cognitive behavioral therapy; Cognitive Therapy; combination therapy; Combined Modality Therapy; combined modality treatment; combined treatment; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Community Clinical Oncology Program; Community Oncology; Compliance behavior; compliance cooperation; Controlled Clinical Trials, Randomized; Coupled; Data; Depression; design; designing; Diagnosis; Diaries; diaries; Diaries (PT); Diaries [Publication Type]; Editorial Comment; Editorial Comment (PT); enroll; Enrollment; Equation; Exclusion Criteria; experience; falls; Fatigue; Female Breast Cancer; Female Breast Carcinoma; General Population; General Public; Health; Hydroxydiazepam; hypnotic; improved; indexing; Insomnia; Insomnia Disorder; Intervention; intervention effect; Intervention Strategies; Intervention Studies; interventional strategy; Investigators; irradiation; Lack of Energy; Link; Maintenance; Maintenances; malignancy; malignant breast neoplasm; Malignant neoplasm of breast; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Mammary Carcinoma of the Female Breast; Measures; Mediating; Mental Depression; Methods; Methyloxazepam; Minority; Modafinil; Modeling; Monitoring, Sleep; Multimodal Therapy; Multimodal Treatment; multimodality therapy; Multimodality Treatment; N, N, 6-trimethyl-2-(4-methylphenyl)imidazo(1, 2a)pyridine-3-acetamide hemitartrate; Needs Assessment; neoplasm/cancer; new approaches; novel approaches; novel strategies; novel strategy; Oncology Programs; Outcome; Oxydiazepam; Pain; Painful; Participant; patient adherence; Patient Compliance; Patient Cooperation; Patients; PBO; Placebos; polysomnographic; Polysomnography; Population; post intervention; Primary Insomnia; Principal Investigator; programs; Programs (PT); Programs [Publication Type]; prospective; Protocol; Protocols documentation; Provigil; Psychotherapy, Cognitive; Published Comment; Publishing; QOL; Quality of life; Questionnaires; Radiation therapy; Radiotherapeutics; Radiotherapy; randomisation; randomization; Randomized; Randomized Controlled Clinical Trials; randomized controlled study; Randomized Controlled Trials; randomized trial; randomly assigned; Receptors, Diazepam; recruit; Recruitment Activity; Regimen; Regression Analyses; Regression Analysis; Regression Diagnostics; Reporting; Research; Research Design; Research Personnel; Researchers; Role; Sample Size; Sampling; screening; Screening procedure; screenings; Selection Bias; Seminal; Severities; sham therapy; Sham Treatment; side effect; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep Disorders; Sleep disturbances; Sleep Hypopnea; sleep measurement; sleep polysomnography; sleep problem; Sleep-Disordered Breathing; Sleeplessness; social role; Somnography; Statistical Regression; study design; Study Section; Study Subject; Study Type; SUBGP; Subgroup; Survey Instrument; Surveys; Symptoms; Temazepam; Temezepam; Testing; Therapeutic; therapeutic efficacy; therapeutically effective; therapy adverse effect; therapy compliance; therapy cooperation; Therapy, Cognition; Time; Tradozone; Trazodone; treatment adverse effect; Treatment Compliance; Treatment Efficacy; Treatment Side Effects; treatment strategy; Universities; Viewpoint; Viewpoint (PT); Work; zolpidem
Project start date: 2008-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01CA126968-04 (2011): $459287
DOES SIRT1 REGULATE MAMMALIAN HEALTH AND LONGEVITY?
A Joseph, Assistant Professor
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R00AG031182-04 from National Institute On Aging
Abstract: Since the 1930s it has been known that a severe reduction in energy intake (caloric restriction, CR) delays the onset of most age-related diseases and extends both mean and maximum lifespan in mammals. Drugs or therapies that mimic these effects would be of enormous benefit to society but their development requires a better understanding of how CR works. It has been proposed that the Sir2/SIRT1 deacetylase is a critical mediator of CR´s effects and indeed, Sir2 is necessary for lifespan extension by CR in simple organisms such as yeast and flies. Small molecules that activate Sir2, such as resveratrol, extend the lifespan of diverse species and are considered potential CR mimetics. Resveratrol has already been shown to prevent a wide variety of disease processes and can reduce all-cause mortality in mammals, making it arguably the most promising candidate for a CR mimetic. At present, however, both the involvement of SIRT1, the closest mammalian Sir2 homolog in CR, and the mechanism of resveratrol´s effects remain topics of heated debate. Resolving these issues is one of the most important endeavors in the aging field today because these findings may lead to new insights into the nature of functional decline and diseases that occur as part of the aging process as well as opportunities for therapeutic interventions. The broad goal of this proposal is to determine the involvement of SIRT1 in the beneficial effects of both CR and resveratrol in mammals using tissue-specific and inducible SIRT1 knockout mice. In each case both cancer-preventive and metabolic effects will be tested in the absence of SIRT1. The specific aims are 1) to determine whether protection from tumorigenesis by CR and/or resveratrol is mediated by SIRT1 in the /pc"´"´* model, 2) to test whether protection from fatty liver and insulin resistance by resveratrol are mediated via SIRT1, and 3) to test whether metabolic adaptations to fasting and CR require SIRT1 in vivo. CR has been shown to be protective against most of the major causes of death and disability in the Western world, including cancer, cardiovascular disease, and the metabolic syndrome. The experiments outlined in this proposal will resolve an important controversy, help to reveal how CR works at the molecular level, and may point the way to the development of effective human therapeutics in a number of disease areas
Keywords: Acute; age related; Aging; Aging-Related Process; Area; Body Weight; Caloric Restriction; Cardiovascular Diseases; Cause of Death; Deacetylase; Deacetylation; Development; Diet; disability; Disease; Energy Intake; Enzymes; Fasting; Fatty Liver; feeding; fly; functional decline; Gene Expression; Genes; Gluconeogenesis; Glucose; glucose output; Glycolysis; Goals; Health; Heating; Hepatic; Hepatocyte; Homologous Gene; Human; improved; In Vitro; in vivo; Incidence; insight; Insulin Resistance; insulin sensitivity; Intestinal Neoplasms; Intestines; Knockout Mice; Lead; Lipids; Liver; Long-Term Effects; Longevity; Lower Organism; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; mimetics; Modeling; Molecular; Mortality Vital Statistics; Mus; Nature; Nutrient; Organism; overexpression; Pattern; Peroxisome Proliferators; Pharmaceutical Preparations; Play; prevent; Preventive; Process; protective effect; receptor; research study; response; Resveratrol; Rodent Model; Serum; small molecule; Societies; Testing; Therapeutic; Therapeutic Intervention; Tissues; tumor; tumorigenesis; Western World; Work; Yeasts
Project start date: 2009-09-15
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5R00AG031182-04 (2011): $236946
HDAC INHIBITION IN CARDIAC HYPERTROPHY AND FAILURE
A Joseph, Chief, Cardiology Division
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5R01HL080144-05 from National Heart, Lung, And Blood Institute
Abstract: Recent studies point to the importance of enzymes that control histone acetylation as stress- responsive regulators of gene expression in the heart. These enzymes function as nuclear integrators that couple diverse upstream signals to govern gene expression. Pharmacological suppression of histone deacetylases (HDACs) is emerging as a promising therapeutic approach in the field of oncology. In this proposal, we will explore HDAC inhibition as a novel therapy in heart disease. Suppression of HDAC activity blunts hypertrophic growth of cardiac myocytes in culture. Preliminary results from our lab with 2 broad-spectrum HDAC inhibitors document significant suppression of hypertrophy in a clinically relevant, aortic banding model. Importantly, despite persistence of afterload stress, HDAC inhibitor-mediated blunting of hypertrophic growth was well tolerated, ventricular size and systolic performance were preserved, and interstitial fibrosis was diminished. Thus, HDAC inhibition (HDACi) appears to blunt pathological growth of the heart. We hypothesize that HDAC suppression with these (and other) small molecules may be an important therapeutic approach in heart disease and worthy of further investigation. Here, we propose studies in animal models of pressure-overload hypertrophy and failure that are designed to determine the utility of HDAC suppressive therapy. In Aim 1, we will study a limited number of structurally diverse HDAC inhibitors to confirm and extend our preliminary studies, determine the effects of these compounds on clinical, functional, and molecular endpoints, and examine the generalizability of this approach to antihypertrophic therapy. In Aim 2, we will examine selected molecular mechanisms we hypotheisze contribute to the salutary effects of HDACi, specifically 1) potentiation of Foxo activity, and 2) suppression of MHC isoform switching. In Aim 3, studies are proposed to define molecular mechanisms that preserve systolic performance, including changes in intracellular Ca2+ homeostasis and the expression and phosphorylation of proteins involved in Ca2+ handling. In Aim 4, we will decipher mechanisms governing diminished fibrosis in HDAC inhibitor-treated hearts, testing the effects of HDAC inhibitors on the biosynthesis and processing of collagens in cultured cardiac fibroblasts and in vivo. Studies proposed here will explore the 3 major effects of HDAC inhibitors observed in our preliminary studies of pressure-stressed myocardium attenuated hypertrophic growth, preserved systolic performance, and diminished fibrogenesis. Together, these studies will provide important insights regarding the utility of HDACi pharmacotherapy as a novel antihypertrophic strategy
Keywords: 21+ years old; 7-(4-(dimethylamino)phenyl)-N-hydroxy- 4, 6-dimethyl-7-oxo-2, 4-heptadienamide; Actins; Adult; adult human (21+); Anabolism; Animal Model; Animal Models and Related Studies; Attention; Attenuated; Autoregulation; base; Biological Preservation; biological signal transduction; biosynthesis; Cancer, Oncology; Cardiac; Cardiac Diseases; Cardiac Disorders; cardiac failure; cardiac hypertrophy; cardiac muscle; Cardiac Myocytes; Cardiac Remodeling, Ventricular; Cardiocyte; cardiomyocyte; Cell Communication and Signaling; Cell Signaling; Chemosensitization; Chemosensitization/Potentiation; Chromatin; chromatin remodeling; Clinical; clinical relevance; clinically relevant; Code; Coding System; COL1A1; COL1A1 gene; COL1A2; COL1A2 gene; Collagen; Collagen Type I; Data; design; designing; Drug Therapy; efficacy testing; Elements; Enzymes; Evaluation; Event; experiment; Experimental Designs; experimental research; experimental study; failure; Failure (biologic function); Fibroblasts; fibrogenesis; Fibrosis; FLR; Gene Expression; Generalized Growth; Genes; Genes, Regulator; Grant; Growth; HDAC; HDAC Agent; HDAC Proteins; Heart; Heart Diseases; heart disorder; Heart failure; Heart Hypertrophy; heart muscle; Heart myocyte; Histone Acetylation; Histone Deacetylase; Histone deacetylase inhibition; Histone Deacetylase Inhibitor; Histones; Homeostasis; HTRPY; Human, Adult; Hypertrophy; In Vitro; in vivo; insight; interstitial; Intracellular Communication and Signaling; Investigation; Investigators; Isoforms; Mediating; model organism; Modeling; Molecular; mouse model; Muscle Cells; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle Cells, Mature; Muscle, Cardiac; Muscle, Heart; Muscle, Involuntary; Muscle, Smooth; myocardial remodeling; Myocardial Remodeling, Ventricular; Myocardium; Myocytes; Myocytes, Cardiac; new therapeutics; next generation therapeutics; novel; novel therapeutic intervention; novel therapeutics; Nuclear; oncology; ontogeny; Performance; Pharmacotherapy; Phosphorylation; Physiological Homeostasis; Potentiation; preservation; Preservation, Biologic; Preservation, Biological; pressure; Pressure; Pressure- physical agent; Prevention; Process; programs; Programs (PT); Programs [Publication Type]; Protein Isoforms; Protein Phosphorylation; Regulator Genes; regulatory gene; Research Personnel; research study; Researchers; response; screening; Screening procedure; screenings; scriptaid; Signal Transduction; Signal Transduction Systems; Signaling; small molecule; Smooth muscle (tissue); Stress; Testing; Therapeutic; tissue culture; Tissue Growth; trans acting element; Transcriptional Regulatory Elements; Trichostatin A; tricostatin A; TSA antibioitc; Type 1 Collagen; Ventricle Remodeling; Ventricular; Ventricular Remodeling; Work
Project start date: 2007-01-15
Project end date: 2011-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
5R01HL080144-05 (2011): $392500
RAPID ULTRA-SENSITIVE THREE DIMENSIONAL PROTEIN STRUCTURE DETERMINATION BY MASS S
A Joseph, Assistant Professor
University Of California Riversidecity: Riverside country: United States (us)
Grant 1R21RR032391-01 from National Center For Research Resources
Abstract: Protein structure is directly connected to proper cellular function and offers a molecular level understanding of the biochemical pathways related to health or disease. This project will develop a method for examining protein structure in the gas phase. This will be accomplished by modifying a state of the art mass spectrometer with a tunable UV laser capable of generating novel protein radicals. Observation of the dissociation patterns of these radical proteins will reveal a series of distance constraints that can be leveraged into three dimensional structures with the aid of molecular dynamics simulations. This method will allow the advantages of speed, sensitivity, and flexibility which are highly optimized for the mass spectrometric analysis of proteins to be applied to the challenging area of structure determination. Therefore, many target proteins which would be intractable for traditional methods will now be viable targets for structure elucidation. Initial systems that will be investigated include proteins that are related to Parkinson´s disease and cancer. It is anticipated that knowledge of the structures of these proteins and factors that influence their structures will greatly facilitate drug development and eventual treatments. PUBLIC HEALTH RELEVANCE Proteins are, at a molecular level, the machines which the human body uses to carry out most biological processes. Revealing the nature of these machines, including their exact structure, is critical to understanding the causes, responses, and potential cures for virtually any disease. This project will develop a novel method for determining the structures of proteins that will greatly expand the number of proteins that can be examined including targets related to cancer and Parkinson´s disease
Keywords: Actins; Area; base; Biochemical Pathway; Biological Process; Biology; Cell physiology; Cells; Charge; Chemistry; Coin; Complex; Coupled; cytochrome c; data acquisition; design; Development; Diagnosis; Disease; Dissociation; drug development; Dyes; Evaluation; flexibility; Fourier transform ion cyclotron resonance; Future; Gases; Goals; Health; Human; Human body; human disease; human MAP3K1 protein; inhibitor/antagonist; ion mobility; Ions; Knowledge; Lasers; Ligands; Macrolides; Malignant Neoplasms; mass spectrometer; Mass Spectrum Analysis; Methodology; Methods; Molecular; Molecular Chaperones; molecular dynamics; Nature; nervous system disorder; novel; Optics; Parkinson Disease; Pattern; Performance; Phase; Photochemistry; Probability; Protein Analysis; protein structure; Proteins; research study; Resolution; response; Series; Speed (motion); Structure; synuclein; System; Techniques; Testing; three dimensional structure; Toxin; Ubiquitin; Vacuum
Relevance: Proteins are, at a molecular level, the machines which the human body uses to carry out most biological processes. Revealing the nature of these machines, including their exact structure, is critical to understanding the causes, responses, and potential cures for virtually any disease. This project will develop a novel method for determining the structures of proteins that will greatly expand the number of proteins that can be examined including targets related to cancer and Parkinson´s disease
Project start date: 2011-08-15
Project end date: 2014-07-31
Budget start date: 15-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-RR-10-009
1R21RR032391-01 (2011): $180348
RESEARCH IN DEVELOPMENT ENDOCRINOLOGY AND METABOLISM
A Joseph, Professor, Chief
Children´s Hospital Bostoncity: Boston country: United States (us)
Grant 5T32DK007699-30 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Project Summary. This training grant in developmental endocrinology and metabolism at Children´s Hospital Boston intends to provide funding for postdoctoral fellows to engage in research training leading to independent careers in academic pediatric endocrinology. Trainees enter the program with either the MD, MD/PhD or occasionally the PhD degree, and are selected from highly qualified pediatric endocrinology fellows at Children´s Hospital. Areas of training include basic investigations in neuroendocrinology, calcium metabolism, carbohydrate pathophysiology, immunoendocrinology, genomic research, thyroid diseases, and bioinformatics, as well as clinical research in obesity, reproductive endocrinology, and carbohydrate metabolism. Training consists of didactic courses, including in quantitative methods and the ethical conduct of research, and an intensive period of individually mentored research. The intended average duration of training is two years. Of the 17 trainees during the past 10 years who have completed this training program, all but 1 are faculty in academic pediatric institutions (1 Associate Professor, 7 Assistant Professors, 8 Instructors). Of these, 7 have had independent NIH K awards, and 1 has an R01. Their record of publication is strong. This program takes advantage of the breadth of scientific expertise of the training faculty within the Division of Endocrinology, as well as in the larger Children´s Hospital Boston community and surrounding Harvard environment. The 21 trainers include 9 pediatric endocrine physician-scientists (including 4 MD/PhDs), 9 physician-scientists of other disciplines, and 3 PhD scientists. Children´s Hospital is the major training site, along with laboratories at Brigham and Women´s Hospital, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Joslin Diabetes Center. Relevance. There is a great shortage of qualified pediatrician-scientists in the United States today, at a time when the potential for scientific breakthroughs in the treatment of pediatric diseases like obesity and diabetes is great. These diseases are a great threat to the future health of our nation´s children. We hope that our program addresses this need by inspiring the early careers of a highly motivated group of pediatric endocrinology trainees immersed in a rigorous and stimulating learning environment
Keywords: Development; Endocrinology; Research
Project start date: 1992-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32DK007699-30 (2011): $253391
CALCINEURIN-MEDIATED REGULATION OF CARDIAC CA2+ CHANNEL
A Joseph, Chief, Cardiology Division
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5R01HL075173-05 from National Heart, Lung, And Blood Institute
Abstract: Perturbation of intracellular Ca2+ signaling and prolongation of the action potential accompany many forms of heart disease and contribute to the pathogenesis of cardiac hypertrophy and failure. The L-type Ca2+ channel is the major mediator of Ca2+ influx into cardiomyocytes and an important determinant of action potential morphology. The role of the L-type channel - the proximal element in Ca2+ signaling - in the pathophysiology of cardiac hypertrophy is poorly characterized. Calcineurin is a cytoplasmic protein phosphatase that mediates hypertrophic signaling in many models of cardiac hypertrophy including our own model of aortic banding in mice. We have reported that activity and abundance of the L-type Ca2+ channel are altered in pressure-overload cardiac hypertrophy through calcineurin-dependent pathways. In this application, we propose to elucidate the underlying mechanisms. This proposal is based on the hypotheses that calcineurin is a regulatory component of the L-type Ca2+ channel complex in cardiac myocytes. We further hypothesize that calcineurin-dependent mechanisms regulate Ca2+ channel function both directly and through altered gene expression. Finally, we hypothesize that these changes - post-translational and transcriptional - contribute to hypertrophic prolongation of the ventricular action potential and consequent arrhythmogenesis. We have collected evidence that calcineurin is a component of the L-type channel macromolecular complex in heart, a finding which will be confirmed and extended in Aim 1. In Aim 2, we will determine whether calcineurin regulates Ca2+ channel function using suppression and heterologous reconstitution strategies. In Aim 3, we will pursue our observation that calcineurin, in addition to regulating channel activity, also regulates transcription of alpha1c, the channel pore-forming subunit. We have cloned a large, 5´ fragment of the alpha1c gene and generated reporter constructs to use in transient transfection experiments. We have also generated "alpha1c reporter" transgenic mice, which we will use to decipher pathways governing a1c expression in vivo. In Aim 4, we will determine whether the mechanisms of calcineurin regulation of Ca2+ channel expression and function examined in Aims 1-3 occur in a clinically relevant, in vivo model of hypertrophy
Keywords: 21+ years old; Action Potentials; Acute; Address; adeno vector; adenovector; Adenoviral Vector; Adenovirus Vector; Adult; adult human (21+); Autoregulation; base; Binding; Binding (Molecular Function); biological signal transduction; Ca Release Channel-Ryanodine Receptor; Calcineurin; Calcium-Ryanodine Receptor Complex; Cardiac; Cardiac Diseases; Cardiac Disorders; cardiac hypertrophy; Cardiac Myocytes; Cardiocyte; cardiomyocyte; Cell Communication and Signaling; Cell Signaling; Chest; clinical relevance; clinically relevant; Complex; Consensus Sequence; ConsensusSequence; Cytoplasmic Protein; Data; Docking; Dysfunction; experiment; experimental research; experimental study; failure; Failure (biologic function); FLR; Functional disorder; Gene Expression; Gene Transcription; Genes; Genetic Alteration; Genetic Change; Genetic defect; genetic promoter element; Genetic Transcription; genome mutation; Genomics; Heart; Heart Diseases; heart disorder; Heart Hypertrophy; Heart myocyte; Homeostasis; HTRPY; Human, Adult; Hypertrophy; In element; in vivo; in vivo Model; Indium; Intracellular Communication and Signaling; Macromolecular Complexes; Mammals, Mice; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; MEF-2; mef2 protein; Messenger RNA; Mice; Modeling; Molecular; Molecular Interaction; Morphology; mRNA; Murine; Mus; Muscle Cells; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle Cells, Mature; muscle-specific enhancer factor-2; Mutate; Mutation; myocyte enhancer factor 2; myocyte-specific enhancer-binding factor 2; Myocytes; Myocytes, Cardiac; NF-AT proteins; NFAT proteins; NFATC proteins; nuclear factor of activated T-cells, cytoplasmic; nuclear factors of activated T-cells; Pathogenesis; pathophysiology; pathway; Pathway interactions; Phosphoprotein Phosphatase; Phosphoprotein Phosphatase-2C; Phosphoprotein Phosphohydrolase; Phosphorylation Site; Physiological Homeostasis; Physiopathology; PP2B; pressure; Pressure; Pressure- physical agent; Promoter Regions; Promoter Regions (Genetics); Promotor Regions; Promotor Regions (Genetics); Protein phosphatase; Protein Phosphatase C; Protein Phosphatase-1; Protein Phosphatase-2A; Protein Phosphatase-2B; reconstitute; reconstitution; Regulation; Reporter; Reporting; research study; RNA Expression; RNA, Messenger; Role; Ryanodine Receptor; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Series; Signal Transduction; Signal Transduction Systems; Signaling; Site; social role; stem; System; System, LOINC Axis 4; Testing; Thorace; Thoracic; Thorax; Transcription; transcription factor NF-AT; Transcription, Genetic; Transfection; Transgenic Mice; Up-Regulation; Up-Regulation (Physiology); Upregulation; Ventricular; Work
Project start date: 2005-08-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5R01HL075173-05 (2009): $334945
ROLES OF HIF-1A IN THE VASCULATURE DURING RECOVERY FOLLOWING CHRONIC SUBLETHAL HY
A Joseph, Professor
Yale Universitycity: New Haven country: United States (us)
Abstract: Our data support the concept of variable responses to brain injury in the preterm infant populafion. We hypothesize that survival and recovery from such injuries is due in part to a coupled neurogenic/vasculoangio-genic response in the neurovascular niche areas of the brain (including the subventricular zone - SVZ) and that HIF-la induced BDNF upregulafion in the vascular system is required for endothelial cell survival, proliferation and vasculogenesis and neural progenitor cell survival, proliferafion and behavioral recovery. A systemafic in vivo and in vitro investigafion of neural stem/progenitor cells (NSCs) and their associated microvasculature in the neurovascular niche areas ufilizing a broad range of techniques is warranted in order to develop rational therapeutic approaches that opfimize recovery. Using murine models of chronic sublethal hypoxia we determined that the survival and recovery of this insult (which mimics the chronic sublethal hypoxia of the preterm infant population) is variable and depends in part upon the responsiveness of the NSCs and microvascular endothelial cells (ECs) in the neurogenic zones. We hypothesize that the upregulation of BDNF in the vascular system may be crucial for the beneficial effect of sensorimoror enrichment in these processes. This project will define the extent to which the HIF-la in the vascular endothelium is responsible for endothelial cell survival, proliferation and vasculogenesis and contributes to neural progenitor cell survival, proliferafion and behavioral recovery. This will be tested by using endothelial HIF-la deficient mice that will be exposed to hypoxia followed by standard or enriched environments. Survival, proliferation differenfiation, and apoptosis of the ECs and NSCs resident in the SVZ will be invesfigated in vivo and in vitro using 2- & 3-dimensional co-cultures. The effects of NPC TrkB paracrine signaling on EC behavior will be assessed in both in vivo and in vitro assays as will white matter angiogenesis and vascular density in hEGFR over-expressing mice and HIF-la modulafion of UCP2 expression, funcfion and mitochondrion number in collaborafion with the other projects in this P01
Keywords: 3-Dimensional; Affect; angiogenesis; Angiogenic Factor; annexin A5; Apoptosis; Apoptotic; Area; base; Behavior; Behavioral; Biochemical; Biological; Biological Assay; Blood Vessels; Brain; brain cell; Brain Injuries; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; caspase-3; cell behavior; Cell Count; Cell Hypoxia; Cell Survival; Cells; Cellular biology; Child; Chronic; Cleaved cell; Clinical; Coculture Techniques; Cognitive; Collagen; Complement; Coupled; CXCR4 gene; Data; density; Development; Disabled Persons; Elements; Endothelial Cells; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Gel; Glial Fibrillary Acidic Protein; handicapping condition; Hemorrhage; Hydrogels; Hypoxia; Immunofluorescence Immunologic; Immunoperoxidase Technics; In Vitro; in vitro Assay; in vivo; Individual; Injury; injury and repair; intraventricular hemorrhage; Mediating; Methods; Mitochondria; Modeling; Molecular; Motor; Mus; nerve stem cell; nestin protein; neurofilament; Neurotrophic Tyrosine Kinase Receptor Type 2; neurovascular unit; novel; Nuclear Pore Complex; Oxygen; Paracrine Communication; PECAM1 gene; Population; Premature Infant; Process; programs; Protocols documentation; Reagent; Recovery; relating to nervous system; repaired; Research Personnel; response; Risk; Role; scaffold; Signal Transduction; Staining method; Stains; stem; Stem cells; Stromal Cell-Derived Factor 1; subventricular zone; Techniques; Testing; Therapeutic; tool; Tubulin; Up-Regulation (Physiology); Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular System; Vascularization; vasculogenesis; Western Blotting; white matter
Relevance: Premature infants are at substantial risk to develop multiple neurodevelopmental handicaps due to chronic lack of adequate oxygenafion. This project will elucidate the undertying responses to this lack of oxygen in brain cells and provide the basis for developing therapeufic responses, abrogafing the effects of this lack of oxygenafion during this crifical period of brain development
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P01NS062686-03_5446 (2011): $238941
THE ROLE OF INFLAMMASOME SIGNALING IN THE PATHOGENESIS OF GONOCOCCAL DISEASE
A Joseph, Assistant Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Abstract: Neisseria gonorrhoeae (gonococcus or GC) is one of the most common sexually transmitted pathogens in the world. N. gonorrhoeae depends on numerous, highly adapted host-pathogen interactions to persist in the human urogenital tract. Localized gonococcal infection is often characterized by paradoxical immunologic findings that include localized inflammation but limited, and non-protective, adaptive immune responses. At the same time, disseminated gonococcal diseases are often associated with mucosal colonization by N. gonorrhoeae that fails to stimulate the host inflammatory response that is a hallmark of localized infections. The mechanisms by which N. gonorrhoeae induces this paradoxical host response are thought to involve both antigenic variation and active manipulation of immune system signaling by the infecting bacteria Gonococcal infection, in human men is associated with production of inflammatory cytokines, including IL-. Ibeta. We have recently found that N. gonorrhoeae induces IL-1 beta production by activation of a host pathogen recognition signaling system known as the inflammasome. Activation of the inflammasome also induces a recently identified program of cell death known as pyronecrosis. Unlike apoptosis, pyronecrosis is a proinflammatory process resulting in the release of intracellular contents which act as inflammatory mediators. The gonococcus activates this pathway more potently than commensal Neisseria species and does so through the the release of factors into the environment, suggesting that activation of the pathway may be related to virulence of N. gonorrhoeae. There are multiple mechanisms by which N. gonorrhoeae may preferentially activate the NLRP3 signaling pathway. In collaboration with several SE STI CRC investigators, we propose a series of studies to investigate the host and pathogen factors involved in activation of this signaling pathway and its involvement in innate and adaptive immune responses to N. gonorrhoeae
Keywords: Accounting; Adjuvant; Affect; aluminum sulfate; Anabolism; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigenic Variation; Antigens; Apoptosis; Bacteria; base; Biology; Bulla; CD4 Positive T Lymphocytes; Cell Death; Cell Line; Cell membrane; Cell physiology; Cells; Collaborations; Complex; Conditioned Culture Media; Cultured Cells; cytokine; Dendritic Cells; Development; Disease; Disease Progression; Environment; Epithelial Cells; Experimental Models; Focal Infection; Genitourinary system; gonococcal porin; Gonorrhea; Haptens; Helper-Inducer T-Lymphocyte; Host Defense; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunologics; immunopathology; Indium; Individual; Infection; Infection prevention; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-18; Invaded; Ions; Lesion; Leukocytes; Lipid A; lipooligosaccharide; Mammalian Cell; Mediating; Membrane; Membrane Proteins; men; microbial; Modeling; monocyte; Mucosal Immune Responses; Neisseria; Neisseria gonorrhoeae; Oligosaccharides; pathogen; Pathogenesis; Pathway interactions; Peptidoglycan; Phagocytes; Phagocytosis; Physiological; picric acid; Pilot Projects; porin; prevent; Process; Production; protein activation; Proteins; Reaction; release factor; Research; Research Personnel; response; Role; Sampling; Series; Sexually Transmitted Diseases; Signal Pathway; Signal Transduction; Structure; success; System; Time; tool; Toxin; Urethra; Vaccines; Variant; Virulence; Virulence Factors; Work
Relevance: This project centers around studies of innate and adaptive immune response to N. gonorrhoeae, a common sexually transmitted pathogen. Understanding the mechanisms underlying the host response to N. gonorrrhoeae is a critical step in the development of effective vaccines that prevent these infections
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5U19AI031496-21_6565 (2011): $255547
Sponsored Links Excellgen http://Excellgen.com
REGULATION OF CELLULAR FUNCTIONS BY CYCLIC NUCLEOTIDE PHOSPHODIESTERASE 8
A Joseph
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R01GM083926-04 from National Institute Of General Medical Sciences
Abstract: It is well recognized that cAMP has important and multiple regulatory roles in the development and function of many different cells. It is also known that cAMP, works largely through activation of cAMP-dependent protein kinases and/or the guanine nucleotide exchange protein, Epac. Moreover, in the last few years it has become clear that specific compartments are present in most cells that serve to organize and regulate specific cAMP-dependent processes in the cells. One of the most important mechanisms by which this regulation occurs is through selective activation or inhibition of distinct isozymes of cyclic nucleotide phosphodiesterases (PDEs) in the cell. Although over 100 different PDEs are known, any single cell type usually expresses less than half a dozen of them and any single compartment even fewer. Our current understanding is that a very small number of PDEs will serve to control a particular pool of cAMP or cGMP. Therefore, different PDEs can easily regulate different processes in the cell. It is the goal of the proposed studies to identify in several different cell types which processes and proteins in that cell are regulated by PDE8A and PDE8B. The PDE8 family is a relatively newly discovered PDE family that is specific for cAMP and has the unusual property of being completely insensitive to isobutylmethylxanthine (IBMX), a highly effective small molecule inhibitor of all other PDEs of this class. As a result PDE8s have until recently not been implicated as major regulators of cellular function. However, recent data from our group now show that they can be very important to regulation of cell function. Our new data shows that in addition to Leydig cells, PDE8s are highly expressed in liver hepatocytes, brown fat cells, and adrenal fasciculata cells. Since we now have available mice having the PDE8A and PDE8B genes disrupted, we are in position to determine the importance of these two PDEs to cellular function, despite the fact that selective small molecule inhibitors are not yet available. Therefore, we propose to determine which of the several functions known to be modulated by cAMP in each of these cell types are regulated by this PDE family and how they do so. The proposed studies will explore the role of a newly discovered and previously unstudied family of cyclic nucleotide phosphodiesterases, the PDE8s on adrenal, liver, and brown fat function. Preliminary evidence suggests that these PDEs are major regulators of cAMP controlled functions in these cell types. It is expected that the proposed studies will tell us which processes are regulated and how the regulation occurs at the molecular level. Just as another specific form of PDE is the target of the drug Viagra, so also it is quite possible that PDE8s may become the targets of drugs useful for treating adrenal, liver and adipose tissue dysfunction once we understand how they function in each of these tissues
Keywords: Abbott brand of sildenafil citrate; Ablation; Acute; Adipocytes; Adipose tissue; Adrenal Cortex; Adrenal Cortex Hormones; Adrenal Glands; Affect; Aldosterone; Animals; base; Brown Fat; Cell physiology; cell type; Cells; Cholesterol Homeostasis; Chronic; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotides; Data; Development; Drug Delivery Systems; Enzymes; expectation; Family; Fatty acid glycerol esters; Functional disorder; Genes; Goals; Guanine Nucleotide Exchange Factors; Hepatocyte; hormone regulation; Hormones; Individual; inhibitor/antagonist; Isoenzymes; leydig interstitial cell; Lipids; Lipolysis; Liver; Measurement; Measures; Mediating; Methods; Molecular; Mus; Pathway interactions; Phosphodiesterase Inhibitors; phosphoric diester hydrolase; Phosphorylation; Physiological; Play; polypeptide; Positioning Attribute; Process; Production; Property; Protein Kinase; Proteins; public health relevance; Regulation; response; Role; small molecule; Steroids; Testing; Thermogenesis; Time; Tissues; Work; Zona Fasciculata
Project start date: 2008-08-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01GM083926-04 (2011): $290502
FOXO: NEGATIVE REGULATOR OF CARDIAC HYPERTROPHY
A Joseph, Professor & Chief
University Of Texas Sw Med Ctr/dallascity: Dallas country: United States (us)
Grant 5R01HL090842-03 from National Heart, Lung, And Blood Institute
Abstract: Disease-related stresses trigger hypertrophic growth of the heart that confers markedly increased risk of failure and malignant rhythm disturbance. By contrast, growth of the heart in response to physiological demand is adaptive and not associated with adverse sequalae. Recently, we have shown that FoxO transcription factors play a key role in regulating cardiac myocyte growth. Conversely, the heart is capable of shrinking substantially under a variety of clinically relevant circumstances, such as mechanical support. Muscle atrophy is an active, energy-requiring process requiring activation of ubiquitin ligases. FoxO transcription governs this "atrogene" response. Thus, FoxO factors are situated at the nexus of multiple forms of cardiac plasticity. Here, we propose a comprehensive analysis of FoxO signaling in cardiac growth and remodeling. Our central hypothesis is that FoxO transcription factors are negative regulators of cardiac growth. We propose to define and manipulate the role of these molecules in 3 major forms of cardiac remodeling 1) pathological hypertrophy stemming from hemodynamic stress; 2) physiological hypertrophy of exercise; and 3) cardiac atrophy from ventricular unloading. Aim 1 To test the functional relevance of FoxO transcription factors during cardiac hypertrophy. Using gain-of-function and loss-of function strategies, we will define and manipulate the actions of FoxO in 2 major forms of cardiac growth, viz. pathological and physiological hypertrophy. Aim 2 To test the functional relevance of FoxO transcription factors during cardiac atrophy. Using a model of heterotopic cardiac transplantation, we will define and manipulate the actions of FoxO in the setting of ventricular unloading. Aim 3 To define and manipulate mechanisms whereby FoxO influences calcineurin and Akt activities, two key mediators of pathological and physiological hypertrophy, respectively. We have evidence that FoxO activation is a robust mechanism of suppressing calcineurin signaling, a major pathway leading to patho- logical cardiac hypertrophy. By contrast, signaling via the PI3K/Akt axis contributes to physiological heart growth, and we have data demonstrating that FoxO is capable of activating Akt. Here, we will decipher mechanisms whereby FoxO targets these major effectors of pathological (calcineurin) and physiological (Akt) cardiac hypertrophy. Cardiovascular diseases are predicted to be the most common cause of mortality worldwide by the year 2020. Recent studies reveal that FoxO transcription factors are situated at the nexus of multiple forms of cardiac plasticity. By determining their role in pathological cardiac growth and atrophy, we will take steps that may lead to novel strategies to prevent heart failure in humans
Keywords: Atrophic; base; Bed rest; Calcineurin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle Progression; clinically relevant; Data; Disease; Employee Strikes; Exercise; Failure (biologic function); Family; forkhead protein; gain of function; Gap Junctions; Genetic Transcription; Growth; Health; Heart; Heart failure; Heart Hypertrophy; Heart Transplantation; hemodynamics; Heterotopic Transplantation; Human; Hypertension; Hypertrophy; inhibitor/antagonist; Injury; insight; Lead; loss of function; Malignant - descriptor; Mechanics; Mediator of activation protein; member; Modeling; Molecular; Morbidity - disease rate; Mortality Vital Statistics; Muscle Cells; Muscular Atrophy; Myocardial; Myocardium; novel strategies; novel therapeutics; Organ; Pathogenesis; Pathway interactions; Physiological; Plastics; Play; Pregnancy; prevent; Process; protein degradation; Proteins; Reaction; response; Risk; Role; Signal Transduction; Skeletal muscle structure; Source; State of Zero Gravity; stem; Stimulus; Stress; Testing; Therapeutic; transcription factor; Travel; ubiquitin ligase; Ventricular; ventricular assist device
Relevance: Cardiovascular diseases are predicted to be the most common cause of mortality worldwide by the year 2020. Recent studies reveal that FoxO transcription factors are situated at the nexus of multiple forms of cardiac plasticity. By determining their role in pathological cardiac growth and atrophy, we will take steps that may lead to novel strategies to prevent heart failure in humans
Project start date: 2009-04-15
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01HL090842-03 (2011): $392500
COORDINATION OF SR PROTEIN PHOSPHORYLATION AND RNA SPLICING
A Joseph, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01GM067969-07 from National Institute Of General Medical Sciences
Abstract: Comparisons of the genomes from humans and lower organisms reveal that the complexity in humans is achieved not by a dramatic increase in the number of genes but by alternative splicing events that stitch together different portions of genes to generate diverse proteins. Correct splicing allows normal healthy function, however, incorrect splicing is linked to many human diseases. For example, muscular dystrophy, ataxias, parkinsonism, neurofibromatosis, psychiatric disorders and cancer have their origins in splicing errors. Splicing reactions are catalyzed by a large macromolecular machine known as the spliceosome. Composed of both RNA and protein, the spliceosome can accurately select the proper splice sites from a considerably large precursor mRNA in healthy cells. The assembly of the spliceosome, the identification of the correct 5´ and 3´ splice sites and the chemical splicing reaction itself is regulated by a large class of splicing factors known as SR proteins. SR proteins contain one or two RNA recognition motifs and a long C-terminal domain rich in numerous arginine-serine dipeptide repeats. The phosphorylation of the RS domain serves many RNA processing functions including splice-site selection, import of SR proteins into the nucleus and export of mature mRNA to the cytoplasm. This project will investigate how two principal families of splicing enzymes uniquely impact SR protein function through regiospecific, multi-site phosphorylation of the RS domains. Using engineered footprinting methods, the directionality of the splicing enzymes will be defined and shown to control which serines in the RS domain are modified. The effects of these selective phosphorylation reactions on SR protein structure and interaction/function within the spliceosome will then be evaluated using kinetic, structural, splicing and cellular assays. The goal is to identify how splicing kinases recognize and phosphorylate specific regions of the RS domains and determine how these chemical modifications impact splicing componentry. Health Relevance Statement Comparisons of the genomes from humans and lower organisms reveal that the complexity in humans is achieved not by a dramatic increase in the number genes but by splicing events that stitch together different portions of genes to generate diverse proteins. Correct splicing allows normal healthy function, however, incorrect splicing is linked to many human neurodegenerative diseases and cancer. We are investigating how the newly identified drug targets for diverse diseases known as splicing enzymes (named SR-kinases) regulate important splicing factors (a specific family of proteins known as SR proteins) which cooperate in the control of alternative splicing reactions important in both health and disease
Keywords: 3` Splice Site; acrosome stabilizing factor; Address; Affinity; Alternative Splicing; Arginine; Ataxia; Biological Assay; Biological Process; C-terminal; Cell Nucleus; Cells; Cellular Assay; Chemicals; chemotherapeutic agent; chemotherapy; Cisplatin; Communities; Complex; Cytoplasm; Dipeptides; Disease; Docking; Down-Regulation; Drug Delivery Systems; Engineering; Enzymes; Event; Family; Funding; Genes; Goals; Health; Hereditary Disease; Human; human disease; Human Genome; interest; Kinetics; Lead; Link; Lower Organism; macromolecular assembly; Malignant Neoplasms; Mental disorders; Messenger RNA; Methods; Modification; Molecular Conformation; mRNA Precursor; Muscular Dystrophies; Mutation; N-terminal; Names; Neurodegenerative Disorders; Neurofibromatoses; novel; Organelles; Pancreatic carcinoma; Parkinsonian Disorders; Pathway interactions; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Protein Binding; Protein Conformation; Protein Family; protein function; Protein Kinase; Protein Splicing; protein structure; Proteins; prototype; public health relevance; Reaction; Refractory; Retinoblastoma; RNA; RNA Processing; RNA Recognition Motif; RNA Splicing; Role; Serine; Site; Specificity; Spliced Genes; Spliceosome Assembly Pathway; Spliceosomes; Structure; Testicular Neoplasms; Testing; treatment strategy; tumor
Relevance: Narrative/Public Health Relevance Statement Comparisons of the genomes from humans and lower organisms reveal that the complexity in humans is achieved not by a dramatic increase in the number genes but by splicing events that stitch together different portions of genes to generate diverse proteins. Correct splicing allows normal healthy function, however, incorrect splicing is linked to many human neurodegenerative diseases and cancer. We are investigating how the newly identified drug targets for diverse diseases known as splicing enzymes (named SR-kinases) regulate important splicing factors (a specific family of proteins known as SR proteins) which cooperate in the control of alternative splicing reactions important in both health and disease
Project start date: 2004-02-01
Project end date: 2012-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01GM067969-07 (2011): $292975
3R01GM067969-05A1S1 (2009): $165402
A Joseph
University Of Chicagocity: Chicago country: United States (us)
Abstract: Cognitive and Practical Biosafety Education for the Host-Pathogen Investigator. This education program seeks to increase awareness of biological hazards encountered in biodefense and emerging disease research laboratories, to provide a scientific basis for assessing risks associated with this research, to provide guidance on recommended practices and to promote the development of required skills to work safely with human pathogens. The object of safety awareness and practice is to assure laboratory and support personnel that¿with proper precautions, equipment and facilities¿biohazardous materials can be handled without undue risk to themselves, their associates, their families, and the environment. Biosafety Fellowship Program. Career development is a strategic goal of the of the GLRCE proposal. A primary objective of the GLRCE is to develop the region´s biodefense infrastructure by enabling more scientists to do work on select agents. The GLRCE has established a career development program for a biosafety professional, a "train-the-trainer" program, that is designed to meet the growing need for individuals capable of leading biosafety programs in government, industry, and academics. Biosafety Fellows participate in the day to day operations of a biosafety officer, and receive specialized training in all aspects of biosafety program development and management in the context of the GLRCE consortium. Fellows undergo rotations with select individuals to learn about specialized biosafety issues, including animal models of disease and working with pathogens at high containment (BSL3), with an emphasis on Select Agent Program management. Fellows assist with and participate in meetings of the University of Chicago Institutional Biosafety Committee (IBC) and Select Agent Institutional Biosafety Committee (SAIBC) where they apply skills related to assessing risks associated with cutting-edge emerging infectious disease and biodefense research. Fellows also play a key role in the development of the GLRCE Cognitive and Practical Biosafety Education for the Host-Pathogen Investigator Course. Professional Certification At completion, fellows will be required to take the American Society for Microbiologists, National Registry of Microbiologists, Specialist in Biosafety certification exam. The GLRCE will support the cost of this exam. Fellows will also be required to write a research thesis concerning their research activities in areas of applied biosafety research, such as inhalation biology, decontamination protocols, infectious dose, environmental stability of pathogenic microorganisms, transmissibility in a variety of animal housing scenarios, efficacy of disinfectants, among other studies. Biocontainment Engineering Internship This will be a hands-on, internship program for engineering students and graduates with engineering degrees to become specialized in the design, construction, operation and maintenance of a biocontainment laboratory
Keywords: Accidents; Advertising; American; Animal Disease Models; Animal Housing; Area; Awareness; base; biocontainment facility; biodefense; Biological; Biology; Biomedical Research; Breathing; career development; Categories; Certification; Charge; Chicago; Cognitive; Communicable Diseases; Communities; Containment; cost; Decontamination; design; design and construction; Development; Discipline; Disease; Disinfectants; Dose; Educational aspects; Educational Curriculum; Electronic Mail; Emerging Communicable Diseases; Employment Status; Engineering; Enrollment; Ensure; Environment; Equipment; experience; Family; Fellowship Program; Goals; Government; graduate student; Hand; hazard; Housekeeping; Human; Human Resources; Hygiene; Individual; Industry; Infectious Agent; Institution; institutional biosafety committee; Intention; Internships; Intervention; investigator training; Laboratories; Laboratory Research; Learning; Maintenance; Measures; Medical; meetings; microorganism; Molecular; Monitor; National Institute of Allergy and Infectious Disease; operation; Parents; pathogen; Play; Process; Program Development; programs; Protocols documentation; Registries; Research; Research Activity; Research Infrastructure; Research Personnel; Resources; Risk; Risk Assessment; Rotation; Safety; safety practice; Scientist; Secure; skills; Social Security Number; Societies; sound; Specialist; Students; Trainers Training; Training; Training and Education; Training Programs; United States; Universities; Vaccination; web site; Work; Writing
Relevance: This education program seeks to increase awareness of biological hazards encountered in biodefense and emerging disease research laboratories, to provide a scientific basis for assessing risks associated with this research, to provide guidance on recommended practices and to promote the development of required skills to work safely with human pathogens
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5U54AI057153-08_5874 (2011): $200466
AGE-RELATED INSULIN RESISTANCE, MUSCLE, AND EXERCISE
A Joseph
East Carolina Universitycity: Greenville country: United States (us)
Grant 5R01AG025205-05 from National Institute On Aging
Abstract: Advancing age is often accompanied by insulin resistance. Relatively little, however, is known concerning the cellular mechanism(s) responsible for age-related insulin resistance in the primary target tissue for insulin action, skeletal muscle. In the current proposal, the hypothesis to be tested is that the insulin signal leading to glucose transport is impaired with the aging process in human skeletal muscle, which induces insulin resistance. Our working hypothesis is that insulin signal transduction is impaired in aged skeletal muscle due to inhibition from increased muscle lipid content and reduced oxidative capacity. As decrements during the aging process can be a consequence of physical inactivity, our secondary hypothesis is that age-related insulin resistance is compensated for with exercise training by enhancing insulin signaling. The following aims will test these hypotheses. Specific Aim 1. Determine if insulin signal transduction is impaired with aging in human skeletal muscle. We will examine if insulin signal transduction in skeletal muscle is impaired with the aging process in humans and if muscle lipid accumulation and reduced oxidative capacity contribute to the decrement. Specific Aim 2. Determine the cellular mechanism(s) by which insulin action is enhanced with physical activity in aged skeletal muscle. We will determine if enhanced insulin signal transduction contributes to the improvement in insulin action seen with endurance- and resistance-oriented exercise training in aged individuals and if a reduction in bioactive muscle lipid content is the unifying mechanism by which physical activity enhances insulin action in the aged, regardless of exercise mode. Specific Aim 3. Determine if muscle oxidative capacity specifically influences insulin signal transduction in human skeletal muscle. With aging there is a decline in muscle oxidative capacity, which can be at least partially compensated for by endurance-oriented physical activity. By using a primary human cell culture system we intend to determine if oxidative capacity directly influences insulin signaling/insulin action
Keywords: 1-Phosphatidylinositol 3-Kinase; Accounting; adult onset diabetes; advanced age; Affect; Age; age dependent; age related; aged; Aged 65 and Over; Aging; Aging Process; Aging-Related Process; ATP[{..}]1-phosphatidyl-1D-myo-inositol 3-phosphotransferase; biological signal transduction; Blood Pressure, High; Body Tissues; Cardiovascular Diseases; cardiovascular disorder; Cell Communication and Signaling; Cell Culture System; Cell Signaling; Data; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Elderly; Elderly, over 65; elders; ethyl 2-(6-(4-chlorophenoxy)hexyl)oxirane-2-carboxylate; etomoxir; Exercise; Exercise, Physical; Funding; Genes; geriatric; Glucose Binding Protein; glucose transport; Glucose Transporter; GLUT4; GLUT4 gene; Hand; Human; Human, General; Humulin R; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; improved; Individual; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Resistance; insulin resistant; insulin signaling; Insulin, Regular; Intracellular Communication and Signaling; Investigators; ketosis resistant diabetes; late life; later life; Lipids; Man (Taxonomy); Man, Modern; maturity onset diabetes; Maturity-Onset Diabetes Mellitus; Mediating; MODY; Muscle; muscle aging; Muscle Fibers; Muscle Tissue; Muscle, Skeletal; Muscle, Voluntary; Myotubes; NIDDM; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Novolin R; older adult; older person; overexpression; oxidation; Phosphatidylinositol 3-Kinase; Phosphatidylinositol-3-OH Kinase; Phosphoinositide 3-Hydroxykinase; Physical activity; PI-3 Kinase; PI-3K; PI3-Kinase; Precipitating Factors; programs; Programs (PT); Programs [Publication Type]; PtdIns 3-Kinase; Public Health; public health medicine (field); Research Personnel; Researchers; Resistance; resistant; Rhabdomyocyte; RNA, Small Interfering; Senescence; senescent; senior citizen; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; siRNA; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal muscle structure; Skeletal Muscle Tissue; Skeletal Myocytes; Small Interfering RNA; strength training; T2D; T2DM; Testing; Tissues; Training; Transport Protein, Glucose; Type 2 diabetes; Type I Phosphatidylinositol Kinase; Type II diabetes; Type III Phosphoinositide 3-Kinase; United States; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Work
Project start date: 2005-09-15
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
PFA/PA: PA-03-156
5R01AG025205-05 (2009): $267210
MOTION ARTIFACT REDUCED SDOCT OF THE ANTERIOR SEGMENT
A Joseph, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R21EY020001-02 from National Eye Institute
Abstract: Accurate quantitative imaging of the cornea is critical for predictable outcomes in corneal based surgical interventions. While long the standard, reflection based corneal topography to assess corneal curvature and refractive power is insufficient in an era when surgical manipulation of the corneal shape is routine and undermines the basis of reflection topography. Laser refractive surgery is one particular corneal intervention that has revealed current inadequacies in measuring the cornea. Over 7 million people in the United States have had some form of laser refractive surgery to reduce their dependence on corrective eye wear. The corneal reshaping that occurs from laser refractive surgery results in excellent visual results for the patient but renders current technologies incapable of accurately measuring the power of the reshaped cornea. Accurate measurement of corneal power is critical in applications such as the prediction of intraocular lens power needed after cataract surgery, an event which this group of patients will invariably encounter as they age into late adulthood. Our proposed development of a motion corrected high-speed spectral domain optical coherence tomography (SDOCT) based device which can directly map corneal surfaces at micron resolution and then accurately convert this data to keratometric values will greatly aid clinical applications dependent on this value. The primary innovations will be the development of novel hardware and software methods to account for involuntary patient motion and for refraction of OCT light within the cornea. A clinical comparison will then be made in patients undergoing laser refractive surgery to compare the measurements made by SDOCT versus existing clinical instrumentation for the measurement of corneal power. We propose to develop an improved ocular anterior segment imaging system using spectral domain optical coherence tomography. If successful, this project could support widespread adoption of SDOCT as the preferred, single-platform anterior segment imaging device in eye care delivery
Keywords: 21+ years old; Accounting; Adoption; Adult; adult human (21+); Age; Algorithms; Anterior; Artifacts; base; care delivery; Cataract Extraction; cataract surgery; Clinical; clinical applicability; clinical application; computer program/software; Computer Programs; Computer software; Cornea; corneal; corneal keratoplasty; Corneal Topography; corneal transplant; Corneal Transplantation; Data; Dependence; design; designing; develop software; developing computer software; Development; Devices; Diagnosis; Dilatation; Dilatation, Pathologic; Doppler OCT; Ectasia; Electromagnetic, Laser; Event; Eye; Eyeball; Grafting, Corneal; Human, Adult; Image; imaging; Imaging Device; Imaging Tool; improved; innovate; innovation; innovative; instrument; instrumentation; Instrumentation, Other; Intervention; Intervention Strategies; interventional strategy; Intraocular lens implant device; Keratoplasty; Lasers; Lenses, Intraocular; Light; Maps; Measurement; Measures; Methods; Metric; Morphologic artifacts; Motion; new technology; novel; OCT Tomography; Operation; Operative Procedures; Operative Surgical Procedures; Optical Coherence Tomography; Outcome; Pathological Dilatation; Patients; Performance; Photoradiation; Procedures; public health relevance; Radiation, Laser; Relative; Relative (related person); Resolution; Shapes; Software; software development; Speed; Speed (motion); Surface; surgery; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Technology; Testing; tomography; Tomography, Optical Coherence; Transplantation, Cornea; United States; Validation; Visual
Relevance: We propose to develop an improved ocular anterior segment imaging system using spectral domain optical coherence tomography. If successful, this project could support widespread adoption of SDOCT as the preferred, single-platform anterior segment imaging device in eye care delivery
Project start date: 2010-01-01
Project end date: 2011-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-06-418
5R21EY020001-02 (2011): $175500
TRAINING IN LUNG MOLECULAR AND CELL PATHOBIOLOGY-PHASE II
A Joseph, Pi/pd
Tulane University Of Louisianacity: New Orleans country: United States (us)
Grant 5T32HL007973-08 from National Heart, Lung, And Blood Institute
Abstract: A solid base of biomedical and basic molecular research in lung diseases has evolved at Tulane University. In 1992, as part of a campus wide strategic plan by Tulane to improve and modernize the lung research activities into the areas of cell and molecular pathobiology Drs. Mitchell Friedman (Principal Investigator) and Arnold Brody (Co-Principal Investigator) were recruited to Tulane University Medical Center. Dr. Friedman is Professor of Medicine and Chief of the Section of Pulmonary Diseases, Critical Care and Environmental Medicine at Tulane University Medical Center. Dr. Brody is currently Professor of Pathology, Vice Chairman of the Department of Pathology at Tulane and Director of the Tulalae Lung Biology Program. With the recruitment of Drs. Friedman and Brody a solid and highly competitive lung disease research program has evolved into the highly collaborative Lung Biology Program at Tulane University over the past seven years. The individual faculty members of the Lung Biology Program represent two departments in the Medical School (Medicine, Pathology and the total amount of all research awards to these investigators is approximately $3 million/year. Furthermore, critical interactive research programs have been developed between the Tulane Ltmg Biology Program and other research centers at Tulane including the Center for Gene Therapy, Department of Biomedical Engineering, Department of Pharmacology, and thc Tulane Cancer Center. The total federal and non-federal monies awarded to the entire faculty on a yearly basis is now approximately $10,200,000 in direct costs. This research award level includes grants from the NIH, DoD, NIOSH, State of LA, associations, and foundations. As an example of productivity of the faculty, for 1998-2002, there have been approximately 113 publications in prestigious journals and numerous presentations at national and international meetings. The main research areas are in mechanisms of lung fibrosis, lung cancer, pulmonary circulation, asthma, COPD, gene therapy, and effects of inhaled toxicants on the lung and airway inflammation mechanisms. The rapid growth of research faculty and research projects in lung ceil and molecular pathobiology at Tulane since 1992 has also been associated with the development of pre-doctoral and post-doctoral training activities. There are presently 23 trainees being mentored by the training faculty. The funding for these trainees are presently derived from individual faculty research grants and contracts, funding from the Tulane Molecular and Cell Biology Program and the Tulane/Xavier Center for Bioenvironmental Research, and foundations and endowments. The Pulmonary, Critical Care and Environmental Medicine Section also provides training for 9 clinical fellows in Pulmonary and Critical Care Medicine. The diversity of the training program is exemplified by the fact that of these trainees, 9 were female, 3 Black, 1 Native American and 7 Asian. The Training program faculty, since 1992, have had 64 post-doctoral trainees obtain academic faculty positions. The wide range of research activities at the cell and molecular level in lung disease, the track record of achievement and training by the faculty, the development of excellent research experience for our trainees, the productivity of the faculty and trainees as evidenced by their publication record and grant funding and the fact that a number of trainees have obtained faculty positions serve as the basis for the submission of this new T-32 training grant to offer funded formalized research training in lung cell and molecular pathobiology. The main objective of this proposal is to train highly-qualified post-doctoral students in basic mechanisms ef lung disease focusing on lung cell and molecular biology. Trainees in the Program, utilizing emerging technologies and new approaches, will acquire the necessary skills to design and conduct basic research studies in pathobiology. We have developed a formalized 2-year training program (a mentored laboratory research project and a formalized core curriculum) to prepare the trainees to develop a successful and independent academic career in research in lung biology
Keywords: Cells; Lung; Molecular; Phase; Training
Project start date: 2001-04-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5T32HL007973-08 (2011): $181187
LIPID METABOLISM IN OBESITY WEIGHT LOSS AND EXERCISE
A Joseph
East Carolina Universitycity: Greenville country: United States (us)
Grant 5R01DK056112-10 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: A key feature of healthy skeletal muscle is the ability to adapt to changes in fuel supply, a phenomenon known as metabolic flexibility. Accordingly, in the skeletal muscle of lean individuals, exposure to lipid results in the activation of a global transcription program that enhances the expression of multiple genes and promotes the oxidation of lipid. Studies from our laboratory and others suggest that this adaptive response is at least partially mediated by the PPARs, a family of lipid-activated nuclear hormone receptors. However, this does not appear to be the case with obesity, as our findings also show that fatty acid oxidation in skeletal muscle is actually depressed with obesity despite elevated extra- and intracellular lipids that should presumably activate the transcriptional machinery which promotes lipid oxidation. These findings suggest that the molecular mechanisms which mediate the up-regulation of lipid oxidation are impaired with obesity, thereby contributing to a state of positive lipid balance. The central focus of this proposal is to test our hypotheses that, A} fatty acid-mediated regulation of oxidative capacity is impaired in skeletal muscle with obesity (Aim 1); SJthat the mechanism responsible involves a defect in PPAR transcriptional activation (Aims 1 & 2) and C| that exercise training, but not weight loss, restores the ability to respond to lipid presence and effectively oxidize lipid (Aims 3 & 4). These hypotheses will together test our central hypothesis that with obesity lipid oxidation in human skeletal muscle is defective which is due, at least in part, to an inability to respond to lipid presence and/or other stimuli (with the notable exception of exercise training) that normally enhance lipid oxidation. Our aims are Aim 1 To determine whether lipid-induced transcriptional regulation of genes involved in lipid oxidation is impaired in skeletal muscle with obesity. Aim 2 To evaluate a possible cause-and-effect relationship between obesity-mediated metabolic inflexibility and PPAR function/dysfunction. Aim 3 To determine whether common clinical interventions restore lipid- induced regulation of lipid oxidation and/or PPAR function in obese subjects. Aim 4 To examine mechanisms by which contractile activity restores lipid-induced regulation of lipid oxidation in obese individuals. In lay terms, this proposal hopes to determine factors that may predispose individuals towards obesity and how interventions (weight loss, exercise) for obesity induce their positive effects
Keywords: Address; adiposity; balance; balance function; Body Weight decreased; body weight loss; Cell Culture Techniques; Clinical; corpulence; corpulency; corpulentia; CSBP1; CSBP2; CSPB1; Data; Defect; depressed; Depressed mood; drug/agent; Drugs; Dysfunction; Enzymes; Equilibrium; Exercise; Exercise, Physical; EXIP; Exposure to; extracellular; Extracellular Signal-Regulated Kinase Gene; Family; fat metabolism; fatty acid oxidation; Fatty Acids; flexibility; Functional disorder; Gene Transcription; Genes; genetic manipulation; Genetic Transcription; Human; Human, General; Impairment; in vivo; Individual; Insulin Resistance; insulin resistant; Intervention; intervention effect; Intervention Strategies; interventional strategy; Intramuscular; Investigators; Laboratories; lipid metabolism; Lipids; Man (Taxonomy); Man, Modern; MAP Kinase Gene; MAPK; MAPK14; MAPK14 gene; Mediating; Medication; Metabolic; Metabolism, Lipids/Lipoproteins/Membrane Constituents; Mitogen-Activated Protein Kinase Gene; Modeling; Molecular; Muscle; Muscle Cells; Muscle Cells, Mature; Muscle Fibers; Muscle Tissue; Muscle, Skeletal; Muscle, Voluntary; Mxi2; Myocytes; Myotubes; Nuclear Hormone Receptor Superfamily; Nuclear Hormone Receptors; obese; obese people; obese person; obese population; Obesity; overexpression; oxidation; Oxidative Regulation; oxidized lipid; p38; p38 MAPK Gene; p38Alpha; pathophysiology; pathway; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Play; PPAR; PRKM14; PRKM15; programs; Programs (PT); Programs [Publication Type]; Regulation; Research Personnel; Researchers; response; Rhabdomyocyte; RNA Expression; Role; sadness; SAPK2A; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal muscle structure; Skeletal Muscle Tissue; Skeletal Myocytes; social role; Stimulus; Stress; System; System, LOINC Axis 4; Testing; Training; Transcription; Transcription Activation; Transcription Regulation; Transcription, Genetic; Transcriptional Activation; Transcriptional Control; Transcriptional Regulation; Up-Regulation; Up-Regulation (Physiology); Upregulation; Weight Loss; weight loss intervention; Weight Reduction; wt-loss
Project start date: 2000-08-15
Project end date: 2012-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2012
5R01DK056112-10 (2010): $287511
QUANTITATIVE MRI OF IRON HOMEOSTASIS, ATROPHY AND TISSUE STRUCTURE IN AD BRAIN
A Joseph, Vice Chairman
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 5R01AG027852-06 from National Institute On Aging
Keywords: acronyms; Address; Affect; Age; Alzheimer`s Disease; Anisotropy; Appearance; Atrophic; Axon; biomarker; Brain; Brain region; brain tissue; Cell Density; Cell membrane; cerebral atrophy; Clinical; clinical Diagnosis; clinically relevant; Complex; Cross-Sectional Studies; Dementia; density; Diagnosis; Differential Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Doctor of Philosophy; drug discovery; Early treatment; Elderly; Evaluation; frontal lobe; Future; Goals; Homeostasis; Image; Impaired cognition; Incidence; indexing; Individual; interest; Intervention; Iron; Laboratories; Longitudinal Studies; magnetic field; Magnetic Resonance Imaging; Measurement; Measures; Medial; mild cognitive impairment; Monitor; Neurodegenerative Disorders; novel; Onset of illness; Pathogenesis; Pathology; Patients; Persons; pre-clinical; Prevalence; programs; Quantitative Evaluations; Research Personnel; Risk; Space Perception; Staging; Structure; Surrogate Markers; Techniques; Temporal Lobe; Testing; Therapeutic; Therapy Clinical Trials; Tissues; United States; Work
Project start date: 2007-04-15
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R01AG027852-06 (2011): $400897
Sponsored Links Excellgen http://Excellgen.com
DYNAMIC REGULATION OF ERYTHROPOIETIN GENE EXPRESSION IN MAMMALS
A Joseph, Assistant Professor
Va North Texas Health Care Systemcity: Dallas country: United States (us)
Relevance: The Potential Impact on Veterans Health Care is identifying specific molecular pathways that can be targeted by novel drug therapies, thereby restoring normal erythropoietin production in a large segment of our veteran patients with chronic anemia
Project start date: 2009-04-01
Project end date: 2012-09-30
Budget start date: 1-APR-2010
Budget end date: 30-SEP-2011
PFA/PA: RFA-BX-08-001
5I01BX000446-02 (2011): $0
QUANTITATIVE MRI OF IRON HOMEOSTASIS, ATROPHY AND TISSUE STRUCTURE IN AD BRAIN
A Joseph, Vice Chairman
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 7R01AG027852-05 from National Institute On Aging
Keywords: acronyms; Address; advanced age; Affect; Age; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Anisotropy; Appearance; Atrophic; Atrophy; Autoregulation; Axon; biomarker; Body Tissues; Brain; brain atrophy; Brain region; brain tissue; Cell Density; Cell membrane; cerebral atrophy; Clinical; clinical Diagnosis; clinical relevance; Clinical Trials, Therapy; clinically relevant; Cognitive decline; Cognitive Disturbance; cognitive dysfunction; Cognitive function abnormal; Cognitive Impairment; cognitive loss; cognitively impaired; Complex; cortical atrophy; Cross Sectional Analysis; Cross-Sectional Analyses; Cross-Sectional Studies; Cross-Sectional Survey; Cytoplasmic Membrane; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; density; Diagnosis; Differential Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Diffusion MRI; diffusion tensor imaging; Diffusion Weighted MRI; Disease; Disease Frequency Surveys; disease onset; Disease Progression; disease/disorder; Disorder; disorder onset; Disturbance in cognition; Doctor of Philosophy; drug discovery; Early treatment; Elderly; Elderly, over 65; elders; Encephalon; Encephalons; Evaluation; Fe element; frontal cortex; frontal lobe; Future; geriatric; Goals; Homeostasis; Image; imaging; Impaired cognition; Incidence; indexing; Individual; interest; Intervention; Intervention Strategies; interventional strategy; Investigators; Iron; Laboratories; late life; later life; long-term study; Longitudinal Studies; magnetic field; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Measurement; Measures; Medial; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods and Techniques; Methods, Other; mild cognitive disorder; mild cognitive impairment; mild neurocognitive disorder; Monitor; MR Imaging; MR Tomography; MRI; Nervous System, Brain; Neurodegenerative Diseases; Neurodegenerative Disorders; neurodegenerative illness; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; NMR Imaging; NMR Tomography; novel; Nuclear Magnetic Resonance Imaging; older adult; older person; Onset of illness; Pathogenesis; Pathology; Patients; perceptual spatial orientation; Persons; Ph.D.; PhD; Physiological Homeostasis; Plasma Membrane; plasmalemma; pre-clinical; preclinical; Prevalence; primary degenerative dementia; Primary Senile Degenerative Dementia; programs; Programs (PT); Programs [Publication Type]; Quantitative Evaluations; Research Personnel; Researchers; Risk; senile dementia of the Alzheimer type; senior citizen; Space Perception; Spatial Discrimination; spatial orientation; spatial orientation (perception); spatial perception; Staging; Structure; Surrogate Markers; Techniques; Testing; Therapeutic; Therapeutic Trials; Therapy Clinical Trials; Tissues; United States; Work; Zeugmatography
Project start date: 2007-04-15
Project end date: 2012-03-31
Budget start date: 1-JAN-2011
Budget end date: 31-MAR-2011
7R01AG027852-05 (2010): $418333
QUANTITATIVE MRI OF MICROSTRUCTURE AND IRON HOMEOSTASIS IN ADHD BRAIN
A Joseph, Vice Chairman
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 7R01EB007656-03 from National Institute Of Biomedical Imaging And Bioengineering
Keywords: 0-11 years old; 21+ years old; 3, 4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1, 2-benzenediol; AD/HD; Address; ADHD; Adolescent; Adolescent Youth; Adult; adult human (21+); After Care; After-Treatment; Aftercare; Age; age dependent; age related; American Psychiatric Association; Anatomic; Anatomical Sciences; Anatomy; anatomy; Anisotropy; Anterior; Architecture; attention deficit hyperactive disorder; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Autoregulation; Axon; base; Biological; Blood Serum; Body Tissues; Brain; Brain region; brain tissue; Cell Density; Cell membrane; Child; Child Development Disorders, Specific; Child Mental Health; Child Psychiatry; Child Youth; Childhood; children; Children (0-21); cingulate cortex; Clinical; Corpus Striatum; Corpus striatum structure; Correlation Studies; Cross Sectional Analysis; Cross-Sectional Analyses; Cross-Sectional Studies; Cross-Sectional Survey; Cytoplasmic Membrane; Data; density; design; designing; Development; Developmental Delay; Developmental Delay Disorders; Diagnosis; Dietary Iron; Diffusion; Diffusion Magnetic Resonance Imaging; Diffusion MRI; diffusion tensor imaging; Diffusion Weighted MRI; Disease; Disease Frequency Surveys; disease severity; disease/disorder; Disorder; Dopamine; Dorsal; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Dysfunction; early adolescence; Encephalon; Encephalons; Engineering / Architecture; Exhibits; Fe element; Ferritin; fMRI; Forcep; Foundations; Functional disorder; Functional Magnetic Resonance Imaging; Gender; Goals; gray matter; harpin; heavy metal lead; heavy metal Pb; High Prevalence; Homeostasis; Human, Adult; Human, Child; Hydroxytyramine; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Image; imaging; Impairment; improved; in vivo; indexing; interest; Investigation; Investigators; Iron; juvenile; juvenile human; Lead; Link; long-term study; longitudinal design; Longitudinal Studies; magnetic field; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Measurement; Measures; Medial; Mediating; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods and Techniques; Methods, Other; Metric; Modeling; Monitor; Morphologic Finding; MR Imaging; MR Tomography; MRI; MRI, Functional; myelination; Nervous; Nervous System, Brain; neural; neural circuit; neural circuitry; neurobiological; Neurobiology; neurophysiology; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Parietal; parietal-frontal circuits; pathophysiology; Pattern; Pb element; pediatric; perceptual spatial orientation; Physical shape; Physiological Homeostasis; Physiopathology; placebo controlled study; placebo controlled trial; Plasma Membrane; plasmalemma; Prefrontal Cortex; Process; Radial; relating to nervous system; Reporting; Research Personnel; Researchers; Role; Sample Size; Science of Anatomy; Science of neurophysiology; Serum; Severities; Severity of illness; social role; Space Perception; Spatial Discrimination; spatial orientation; spatial orientation (perception); spatial perception; Specific qualifier value; Specified; Statistical Correlation; striatal; Striate Body; Striatum; substantia alba; substantia grisea; Supplementation; Symptoms; Techniques; Testing; Thick; Thickness; Time; Tissues; white matter; youngster; Zeugmatography
Relevance: Attention-Deficit/Hyperactivity Disorder (ADHD) is the most studied condition in child mental health, reflecting its high prevalence (3% to 6% of children) and association with significant lifelong impairment. The ability to quantitatively characterize in vivo the biophysical and neurophysiological changes that occur in ADHD brain has the potential to improve our ability to better understand, diagnosis and assess treatment of this disorder
Project start date: 2009-05-15
Project end date: 2011-04-30
Budget start date: 1-OCT-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
7R01EB007656-03 (2010): $476102