MECHANISMS OF ISCHEMIC NEONATAL BRAIN INJURY
M Donna, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5P50NS035902-14 from National Institute Of Neurological Disorders And Stroke
Abstract: The studies outlined in this proposal form a cohesive theme focused on ischemic injury and recovery mechanisms in perinatal hypoxia-ischemia. These projects arose as an outgrowth of the last cycle, but with new and exciting directions for the projects. We will now turn our attention to the long-term repair and recovery mechanisms. Our multi-disciplinary approach is maintained in this renewal with the human research project and three laboratory projects that all inform each other and are supported by two cores. The administrative core provides budgetary oversight, training and data management, while the technology core provides a central facility for both the human and laboratory studies for MR imaging and development as well as a repository for MRI development. In Project 1 "White matter injury as predictor of outcome in neonatal brain injury", we plan to focus on the injury to white matter and to correlate the damage in major white matter pathways with neurodevelopmental outcome. We will utilize short echo 3D MR spectroscopic imaging (SEMRSI) to detect changes in metabolites relevant to the injury process, and we also propose to apply high angular resolution diffusion tensor imaging (HARDI) to detect small changes in water diffusion parameters (diffusivity and anisotropy). In Project 2 "Role of Vascular Endothelial Growth Factor (VEGF) in recovery after ischemic neonatal brain injury", we will test whether VEGF plays a critical role in long-term recovery after neonatal stroke by promoting angiogenesis and neurogenesis. In Project 3 "Effects of polyphenols on neonatal Hypoxia-ischemia (H-l) brain injury", we hypothesize that exposure to polyphenols from pomegranate juice as well as the specific polyphenol, resveratrol, will protect the neonatal brain against the acute effects of H-l. In addition, we hypothesize that delayed injury that occurs in the setting of neonatal H-l including axonal injury and regeneration will also be responsive to polyphenols. In Project 4 "Tissue repair in two models of acute neonatal brain injury", we will focus on the repair process in two distinct models of neonatal brain injury - neonatal bacterial meningitis and transient middle cerebral artery occlusion. The two models share common features during the acute phase, such as tissue inflammation and apoptotic neuronal cell death; very little is known about the repair process in these models. These projects are all relevant to human disease as they will bring us closer to therapies for neonatal brain ischemia. RELEVANCE TO PUBLIC HEALTH Achieving these goals will ultimately result in improved care and outcome in encephalopathic neonates, and potential therapies aimed at the repair process after neonatal ischemic events
Project start date: 1998-04-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5P50NS035902-14 (2011): $976939
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to M Donna
INTEGRIN SIGNALING IN THE TRABECULAR MESHWORK
M Donna, Professor
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01EY020490-02 from National Eye Institute
Abstract: This is a new application for a R01. The long-term objective of this grant is to identify integrin signaling mechanisms that can be used as therapeutic targets to control and lower intraocular pressure. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the trabecular meshwork (TM). Although a number of physiological factors are known to regulate outflow facility, one of the key factors that have emerged as an important regulatory mechanism for outflow facility is the contractile properties of the TM. At the present, it is unclear what molecular events regulate contractility in the TM. Studies from our laboratory have shown that the signaling properties of bioactive fragments from the extracellular matrix (ECM) and their receptors (integrins) can be used to regulate the contractility of the TM and increase outflow facility in cultured anterior segments. In particular we have shown that a bioactive domain from fibronectin called the HepII domain activates a ?4?1 integrin signaling pathway that decreases cell contractility in cultured TM cells. Our preliminary data strongly supports the hypothesis that manipulation of integrin signaling pathways in the TM that modify cellular contractility can be used to regulate outflow facility. The objective of this research is to identify possible ways to target integrin signaling pathways in the TM in order to increase outflow facility. To this end, we propose three approaches to activate the ?4?1 signaling pathway in cultured anterior segments. First, use lentiviral vectors to express a mini-HepII gene in the TM. Second, over express a constitutively activated ?4 integrin subunit in the TM. Third, express peptides from the cytoplasmic domain of the ?4-subunit or the integrin binding protein, paxillin which disrupt cell adhesion and decrease cell contractility. The studies proposed in this application will not only enhance our understanding of the role of integrin signaling in the TM, but it will identify new ways to target cell contractility in the TM. Glaucoma is the second most common cause of blindness in the U.S. and the most common cause of blindness among African-Americans. Increased intraocular pressure (IOP) is a common risk factor for glaucoma. The goal of this project is to identify signaling pathway(s) that can be activated to reduce IOP and be used as potential targets to treat glaucoma
Keywords: Actins; Active Sites; Affect; African American; Amino Acids; Anterior; Aqueous Humor; base; Binding (Molecular Function); Binding Proteins; Binding Sites; Blindness; Cell Adhesion; Cells; Cytoplasmic Tail; Cytoskeleton; Data; design; Down-Regulation; Effectiveness; Event; Extracellular Matrix; Fibronectins; Genes; Glaucoma; Goals; Grant; Heparin; Human; Integrin Binding; Integrin Signaling Pathway; Integrins; Laboratories; Lead; Lentivirus Vector; Ligands; Lymphocyte Activation; Molecular; Monkeys; Monomeric GTP-Binding Proteins; Mutation; Organ Culture Techniques; paxillin; Peptides; Perfusion; Physiologic Intraocular Pressure; Physiological; Play; Property; receptor; Regulation; Research; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; therapeutic target; Trabecular meshwork structure
Project start date: 2010-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01EY020490-02 (2011): $352675
DISCOVERY OF FUNCTIONAL VARIANTS IN TYPE 2 DIABETES GENES IN MEXICAN AMERICANS
M Donna, Scientist
Texas Biomedical Research Institutecity: San Antonio country: United States (us)
Grant 5U01DK085524-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The prevalence of type 2 diabetes (T2DM) has been increasing at epidemic proportions worldwide including significantly increased rates among United States (US) minority populations such as Mexican Americans. To date, knowledge about the genetic determinants of T2DM is very limited. However, recent genome-wide association studies (GWASs) of T2DM in populations of European ancestry have localized 19 putative genomic regions that may harbor relevant susceptibility loci. These initial findings reflect association signals related to common variants. The identity of the underlying causal genes and their functional variants still remain unknown. Efforts to replicate the original association findings in ethnically diverse populations have not been universally successful, perhaps due to issues such as allele frequency and linkage disequilibrium (LD) differences. Therefore, an exhaustive resequencing-based search of the genomic regions surrounding these original genetic signals in ethnically diverse populations is required to help identify the underlying causal genes and their likely functional variants. In the proposed project, we will attempt to identify causal variants influencing T2DM based on existing localizations obtained from GWA studies using data/samples from five Mexican American family studies in San Antonio (N = 5,638). To fulfill our objective, we will identify all sequence variants in an approximately 250 kb region around the single nucleotide polymorphism (SNP) of interest by deep resequencing of the selected 16 T2DM candidate gene regions identified from GWASs (Aim 1). Using a highly efficient family-based design, we will then identify the most likely functional variants influencing risk of T2DM in 1,000 effectively sequenced individuals using a novel statistical prioritization method, Bayesian quantitative trait nucleotide (BQTN). The most strongly associated 50 SNPs from Aim 2 will then be typed in a sample of 5,030 adults to confirm their association with T2DM (Aim 3). In addition, we will examine whether the variants found to be significant in adults affect T2DM related traits in ~600 non-diabetic children. To carry out the study, advanced next generation sequencing techniques will be combined with unique computationally intensive statistical genetic techniques to predict those variants most likely to play causal roles in T2DM risk. RELEVANCE Identification of T2DM susceptibility genes in Mexican Americans will have major public health relevance in the US and in developed and developing countries. Identification of genes causally involved in T2DM risk may dramatically speed the quest for novel drug targets and improved pharmacologic interventions. Genetic findings in Mexican Americans may help explain health disparities among US populations
Keywords: Adult; Adult Children; Affect; base; Bayesian Method; Beta Cell; Birth Weight; Body mass index; Candidate Disease Gene; Cell physiology; Child; cost; Data; design; Developed Countries; Developing Countries; DNA; DNA Resequencing; Drug Delivery Systems; Epidemic; European; Extended Family; Family; Family Study; Gene Frequency; Genes; Genetic; genetic association; Genetic Determinism; Genetic Techniques; genetic variant; genome wide association study; Genomics; Genotype; health disparity; improved; Individual; Insulin Resistance; interest; Intervention; Knowledge; Linkage Disequilibrium; Lymphocyte; Measures; member; Mexican Americans; Minority; next generation; non-diabetic; Non-Insulin-Dependent Diabetes Mellitus; novel; Nucleotides; Obesity; Participant; Play; Population; Population Heterogeneity; Prediabetes syndrome; Predisposition; Prevalence; Probability; Proxy; public health relevance; Risk; Role; Sample Size; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Speed (motion); Susceptibility Gene; TCF7L2 gene; Techniques; trait; United States; Variant; waist circumference
Project start date: 2009-09-20
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-DK-09-004
5U01DK085524-03 (2011): $515276
DEVELOPMENT STUDIES OF THE INNER EAR
M Donna
Purdue University West Lafayettecity: West Lafayette country: United States (us)
Grant 5R01DC002756-16 from National Institute On Deafness And Other Communication Disorders
Abstract: The goal of our research is to understand the timing and molecular mechanisms that control patterning and cell fate specification in the developing inner ear. The inner ear, unique to vertebrates, houses the peripheral receptors for the sensations of hearing and balance. It is composed of a complex three-dimensional arrangement of constituent cells which includes neurons, receptors grouped into distinct sensory organs, and non-sensory tissues that form the ducts, tubules and specialized secretory epithelia needed for proper homeostasis of the fluid components. In humans and animal models, disruption of the precise morphology of the inner ear due to congenital defects or disease can result in deafness and/or to difficulties with balance and equilibrium. Our efforts to understand the fundamental defects that result in inner ear abnormalities are focused on both the normal processes of development and on the cascade of events that can arise as a result of specific genetic defects. In this study, we focus on Wnt signaling. This family of signaling molecules has been highly conserved during evolution, and is linked to many aspects of development including control of cell proliferation, cell fate specification, morphogenetic movements, axon guidance and orientation of cells along the body axis. We have completed a comprehensive mapping of the spatial and temporal expression patterns of 28 Wnt-related genes during development of the avian inner ear. Our survey included ligands, receptors and secreted inhibitors. The data have led to several hypotheses about the role of Wnts in different aspects of ear development. The Specific Aims are (1) to explore the function of Wnt/2-catenin signaling as a switch between auditory and vestibular (macular) sensory organ fates in the cochlear duct; (2) to explore the function of Wnt signaling as a repulsive axon guidance cue in the developing inner ear; and (3) to explore the function of radial gradients of Wnt-related molecules across the auditory sensory epithelium. Our findings may provide baseline data for therapeutic strategies to direct stem cells along different developmental fates for repair or replacement of damaged inner ear cells. Our research program uses the chicken embryo to study the molecular pathways underlying development of the inner ear. The long-term goal of our research is to determine whether the molecules we identify may be linked to genetic causes of congenital deafness in humans, with the hope that this knowledge might be applied to therapeutic treatments aimed at the regeneration or repair of inner ear cells
Keywords: Animal Model; Animal Models and Related Studies; Auditory; Autoregulation; Aves; Avian; Axon; axon growth cone guidance; axon guidance; balance; balance function; Basilar Papilla; biological signal transduction; Birds; Birth Defects; body movement; Body Tissues; Candidate Disease Gene; Candidate Gene; Cell Communication and Signaling; cell fate specification; Cell Growth in Number; Cell Multiplication; Cell Polarity; Cell Proliferation; Cell Signaling; cell type; Cells; cellular polarity; Cellular Proliferation; Chickens; Co-culture; Cochlear duct; Cocultivation; Coculture; Coculture Techniques; Complex; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; congenital deafness; Congenital Defects; Congenital Deformity; Congenital Malformation; Corti Cell; Cues; Data; Deafness; Defect; Development; Disease; disease/disorder; Disorder; Duct; Duct (organ) structure; Ductus Cochlearis; Ear; ear hair cell; Ear structure; Ear, Internal; Ectopic Expression; Embryo; Embryonic; Epithelium; Equilibrium; Esthesia; Event; Evolution; experiment; Experimental Organism; experimental research; experimental study; Family; fluid; gain of function; Gallus domesticus; Gallus gallus; Gallus gallus domesticus; Ganglia; Ganglion Cysts; Ganglionic Cysts; Ganglions; Gene Delivery; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; Hair; Hair Cells; Hearing; hearing perception; Homeostasis; Housing; Human; Human, General; inhibitor; inhibitor/antagonist; inner ear; innervation; Intracellular Communication and Signaling; knock-down; Knowledge; Laboratory Organism; Labyrinth; Ligands; Link; liquid; Liquid substance; loss of function; macula; macular; Man (Taxonomy); Man, Modern; Maps; Media, Scala; Mediating; Methods; model organism; Molecular; Molecular Genetic Abnormality; Morphology; Mother Cells; Movement; Mutation; Myxoid cyst; Natural regeneration; Nerve Cells; nerve supply; Nerve Unit; Nervous System; Nervous system structure; Neural Cell; Neural Ganglion; Neurocyte; Neurologic Body System; Neurologic Organ System; neuronal; Neurons; NRVS-SYS; Organ; Otic Vesicle; overexpression; pathway; Pathway interactions; Pattern; Peripheral; Physiological Homeostasis; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Primordium; Process; Progenitor Cells; programs; Programs (PT); Programs [Publication Type]; Quelling; Radial; receptor; Receptor Protein; regenerate; Regeneration; repair; repaired; Research; research study; RNA Interference; RNA Silencing; RNA Silencings; RNA, Small Interfering; RNAi; Role; Scala Medias; Sensation; Sensory; Sequence-Specific Posttranscriptional Gene Silencing; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; siRNA; Small Interfering RNA; social role; sound perception; Source; Specific qualifier value; Specified; Stem cells; Survey Instrument; Surveys; Testing; Therapeutic; Time; Tissues; To specify; Transcript; Transmission; transmission process; vertebrata; Vertebrate Animals; Vertebrates; Virus; Viruses, General; Width
Relevance: Our research program uses the chicken embryo to study the molecular pathways underlying development of the inner ear. The long-term goal of our research is to determine whether the molecules we identify may be linked to genetic causes of congenital deafness in humans, with the hope that this knowledge might be applied to therapeutic treatments aimed at the regeneration or repair of inner ear cells
Project start date: 1995-08-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-127
5R01DC002756-16 (2011): $339900
5R01DC002756-15 (2010): $360087
A2ALL- PATIENT SAFETY SYSTEM IMPROVEMENTS IN LIVING DONOR LIVER TRANSPLANTATION
M Donna, Research Assistant Professor
Northwestern Universitycity: Chicago country: United States (us)
Grant 1R01DK090129-01A1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The Centers for Medicare and Medicaid Services have become increasingly focused on improving healthcare safety and quality while decreasing costs and adopted a policy of no longer reimbursing hospitals for the costs of treating designated preventable inpatient complications. Living donor liver transplantation (LDLT), involves complex systems and processes of care that are particularly vulnerable to medical errors and preventable complications. In fact, complication rates for LDLT donors and recipients are 20-30% and 75%, respectively, of which 70% are deemed preventable. Effective elimination of preventable complications in LDLT will require careful attention to the vulnerabilities in the systems and processes of care for LDLT donors and recipients. Prevention of such events is especially important when caring for living donors, given that they are healthy volunteers undergoing a major procedure purely for altruistic reasons without any direct benefit. The importance of donor safety is magnified in light of the two LDLT donor deaths, earlier this year in the United States. Considerable advances in reducing medical errors and preventable complications have already been achieved. In the field of transplantation, new protocols such as those used to confirm ABO compatibility between the donor and recipient have been highly effective. This study proposes to apply the proactive, systematic, and comprehensive approaches successfully used in other high risk industries and adapted for healthcare, to LDLT system and processes of care. The proactive, systematic, and comprehensive identification of potential vulnerabilities will permit the development and implementation of solutions designed to mitigate these vulnerabilities and, thus, reduce medical errors and preventable complications in LDLT. This study will build on the considerable strengths of the Adult-to-Adult Living Liver Transplant Cohort Study (A2ALL) as an ancillary study of the A2ALL consortium. A2ALL has recognized the importance of providing safe and reliable LDLT care, and has made donor safety a secondary aim and fully supports this study. Seven of the nine A2ALL centers will be involved in this study either as an intervention or a control center, thus, representing more than 50% of all LDLTs performed in the US. This study is novel and innovative, because it seeks to shift the paradigm of response to medical errors to a proactive approach of assessing and improving the safety of systems and processes to prevent medical errors in living donor liver transplant (LDLT) before they occur. This study will apply adapted methods successfully applied by other high risk industries to generate new and important information about LDLT safety. LDLT provides an excellent opportunity to fully assess the mechanisms of medical errors and preventable complications as there is little risk of confounding by donor co-morbid conditions. Living donor liver transplantation (LDLT), involves complex systems and processes of care that are particularly vulnerable to medical errors and preventable complications. This ancillary study of the Adult-to- Adult Living Liver Transplantation Cohort Study (A2ALL) will focus on conducting a proactive, systematic, and comprehensive assessment of the vulnerabilities in the systems and process of LDLT care to reduce medical errors and preventable complications thereby improving the safety of LDLT care. This project will address an important gap in the knowledge needed to achieve high quality and safe LDLT care of patients by developing a process to 1) proactively, systematically and comprehensively identify areas of vulnerabilities in LDLT care that can result in medical errors, 2) design and implement solutions to mitigate these weaknesses, and 3) evaluate the effectiveness of these solutions to improve the safety of LDLT care by measuring clinical and process outcomes before and after solution implementation across four intervention and three control centers. NOTE The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers´ commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion
Keywords: Address; Adopted; Adult; Air; Ancillary Study; Area; Attention; Caring; Cessation of life; Clinical; Clinical Trials Data Monitoring Committees; Cohort Studies; Collaborations; Complex; Complication; cost; Critiques; Deep Vein Thrombosis; design; Development; Effectiveness; Embolism; Event; Face; Failure (biologic function); Healthcare; healthy volunteer; high risk; Hospital Costs; improved; Industry; innovation; Inpatients; Intervention; Knowledge; Lead; Life; Light; liver transplantation; Living Donor Liver Transplantation; Living Donors; Lung; Measures; Medical Errors; Medical Records; meetings; Methods; novel; nuclear power; Online Systems; Outcome; Patient Care; patient safety; Phase; Plant Roots; Policies; Positioning Attribute; Postoperative Hemorrhage; prevent; Prevention; Procedures; Process; Protocols documentation; Published Comment; Reporting; response; Risk; Safety; Solutions; System; Transplantation; United States; United States Centers for Medicare and Medicaid Services
Relevance: Living donor liver transplantation (LDLT), involves complex systems and processes of care that are particularly vulnerable to medical errors and preventable complications. This ancillary study of the Adult-to- Adult Living Liver Transplantation Cohort Study (A2ALL) will focus on conducting a proactive, systematic, and comprehensive assessment of the vulnerabilities in the systems and process of LDLT care to reduce medical errors and preventable complications thereby improving the safety of LDLT care. This project will address an important gap in the knowledge needed to achieve high quality and safe LDLT care of patients by developing a process to: 1) proactively, systematically and comprehensively identify areas of vulnerabilities in LDLT care that can result in medical errors, 2) design and implement solutions to mitigate these weaknesses, and 3) evaluate the effectiveness of these solutions to improve the safety of LDLT care by measuring clinical and process outcomes before and after solution implementation across four intervention and three control centers. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers´ commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion
Project start date: 2011-09-01
Project end date: 2015-05-31
Budget start date: 1-SEP-2011
Budget end date: 31-MAY-2012
PFA/PA: PAR-09-247
1R01DK090129-01A1 (2011): $804492
AN ADHERENCE AND DEPRESSION INTERVENTION FOR PATIENTS DURING HEPATITIS C THERAPY
M Donna, Assistant Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5K23DK089004-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The candidate, a clinical health psychologist, seeks to develop her career into that of an independent investigator performing clinical research with patients with hepatitis C viral (HCV) infection who are undergoing antiviral therapy. The prevalence of mental health disorders in patients with HCV, coupled with the adverse side effects of antiviral therapy, underscores the need for research to develop behavioral programs that can target these issues. The candidate´s long-term career goal is to (1) develop psychosocial interventions that enhance HCV treatment outcomes by improving medication-taking adherence and side effect management of neuropsychiatric and other antiviral side effects; and (2) evaluate these interventions in methodologically-robust randomized controlled trials. The mentored research project in this proposal fits into this overarching research program by conducting a pilot feasibility study to adapt and test an intervention to tackle two common challenges of antiviral therapy-depression and nonadherence. The study will be conducted in two phases first, the Cognitive-Behavioral Treatment for Adherence and Depression (CBT-AD) for HIV intervention will be adapted to meet the needs of HCV patients on antiviral therapy; and second, the new CBT-AD for HCV intervention will be piloted with a sample of patients undergoing antiviral therapy in a small randomized clinical trial to examine feasibility, acceptability, and effect size estimates. The data will demonstrate that conducting group intervention protocols and testing them in clinical trials is feasible and acceptable to patients, and will provide preliminary data to conduct a large, multisite efficacy trial. To acquire the new knowledge and skills to achieve these long-term goals, a four year career and research development plan is proposed. The candidate will receive closely mentored research training by a team of experts in HCV treatment, adherence, behavioral interventions, and randomized clinical trials. Conducting research, under close supervision of mentors, will provide a critical training vehicle for the candidate to develop skills in qualitative methodology, intervention development, and clinical trial conduct. This hands-on training will be augmented by didactics and intensive training workshops led by experts in intervention development and clinical trials. A career advisory board, comprised of national and local experts, has been assembled to provide annual review of the candidate´s progress. If funded by the NIDDK, this K23 award will serve as the platform from which to launch a program of research that applies behavioral and psychological knowledge and techniques to improve the treatment outcomes of patients with HCV. The career development, training plan, and research activities proposed by the candidate will be conducted through the UNC Liver Program, a well-established program devoted to exceptional patient care and state-of-the-art clinical research in antiviral therapy for HCV. The candidate is also surrounded by an outstanding institutional environment and resources at UNC to acquire the clinical research and academic skills needed to become an independent and successful, NIH clinical investigator. Chronic hepatitis C viral (HCV) infection affects nearly 4 million Americans, leading to advanced liver damage and cancer, killing 10,000 Americans each year, and costing our country $700 million dollars each year in healthcare costs. From a public health perspective, it is critical that all persons infected with HCV have the opportunity to successfully complete medical treatment that can cure HCV, and prevent advanced liver problems, deaths, and high healthcare costs. The goal of this project is to develop and test an intervention to treat depressive symptoms and adherence problems, two major challenges to HCV medical treatment, which may, in turn, increase treatment success rates
Keywords: Address; Adherence (attribute); Adverse effects; Affect; American; Antiviral Agents; Antiviral Therapy; Attenuated; base; Behavior Therapy; Behavioral; career; career development; Cessation of life; Chronic Hepatitis C; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Cognitive Therapy; Combined Modality Therapy; Comorbidity; Complex; Compliance behavior; Conduct Clinical Trials; cost; Country; Coupled; Data; Data Collection; depressive symptoms; Development Plans; Disease; Dose; Early treatment; Educational workshop; efficacy trial; Enrollment; Environment; Feasibility Studies; Feedback; Focus Groups; Foundations; Funding; Goals; group intervention; Health; Health Benefit; Health Care Costs; Hepatitis C; Hepatitis C Therapy; High Prevalence; HIV; improved; Individual; instrument; Interferons; Intervention; Intervention Trial; Interview; Killings; Knowledge; Lead; Learning; Life; Liver; Malignant Neoplasms; Manuals; Measures; Medical; medication compliance; meetings; member; Mental Depression; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Needs Assessment; neuropsychiatry; Oral; Participant; Patient Care; patient population; Patients; Persons; Pharmaceutical Preparations; Phase; Pilot Projects; Population; Prevalence; prevent; primary outcome; Procedures; Program Evaluation; programs; Protease Inhibitor; Protocols documentation; Provider; psychologic; Psychologist; psychosocial; public health medicine (field); public health relevance; Randomized Clinical Trials; Randomized Controlled Trials; Reaction; Recruitment Activity; Research; Research Activity; research and development; Research Personnel; Research Project Grants; Research Training; Resources; response; Ribavirin; Risk; Sampling; Schedule; Self Management; Side; skills; Staging; standard care; Substance abuse problem; success; Supervision; Techniques; Testing; therapy development; Time; Training; treatment adherence; Treatment Effectiveness; Treatment outcome; United States National Institutes of Health; Viral; viral resistance; Virus Diseases
Relevance: Chronic hepatitis C viral (HCV) infection affects nearly 4 million Americans, leading to advanced liver damage and cancer, killing 10,000 Americans each year, and costing our country $700 million dollars each year in healthcare costs. From a public health perspective, it is critical that all persons infected with HCV have the opportunity to successfully complete medical treatment that can cure HCV, and prevent advanced liver problems, deaths, and high healthcare costs. The goal of this project is to develop and test an intervention to treat depressive symptoms and adherence problems, two major challenges to HCV medical treatment, which may, in turn, increase treatment success rates
Project start date: 2010-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-09-043
5K23DK089004-02 (2011): $140494
TRANSLATIONAL RECODING OF UGA AS SELENOCYSTEINE IN SELENOPROTEIN SYNTHESIS
M Donna, Professor
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 5R01DK085391-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Selenium is an essential micronutrient that exerts many important health benefits. The nutritional requirement for selenium is likely due to its function in selenoproteins, which contain the element in the form of selenocysteine (Sec), the 21st amino acid. Mammalian selenoproteins perform critical functions in thyroid hormone metabolism, anti-oxidant defense inflammation, and development. The goal of this proposal is to understand the mechanism of selenoprotein synthesis and identify the determinants that control the efficiency of this process. The incorporation of Sec into the growing polypeptide chain requires a translational recoding event in which the UGA stop codon is read as Sec. In eukaryotes, the recoding of UGA as Sec depends on the Sec Insertion Sequence (SECIS) in the 3´ untranslated region of the selenoprotein mRNA. The SECIS interacts with SECIS Binding Protein 2 (SBP2) and ribosomal protein L30, which play critical roles in the recoding mechanism. We defined a novel bipartite RNA- binding domain in SBP2 and showed that a naturally occurring point mutation in this domain, which is associated with hypothyroidism in humans, alters the SECIS-binding activity of the protein and selectively affects the expression of a subset of selenoproteins, including those involved in thyroid hormone metabolism. Multiple lines of evidence support the hypothesis that L30 is involved in UGA recoding but how this ribosomal protein functions in Sec incorporation is not known. Our studies suggest that there is a dynamic exchange of SBP2 and L30 on the SECIS and that the two proteins act sequentially during UGA recoding. Such a stepwise assembly mechanism may enhance the efficiency of selenoprotein synthesis by preventing nonproductive interactions and orchestrating a specific series of events. In this project, we propose to 1) understand the molecular basis for the SBP2SECIS interaction; 2) test the hypothesis that SBP2 dictates the expression of the selenoproteome in vitro and in vivo; and 3) elucidate the function of L30 in selenoprotein synthesis in mammalian cells. The information and molecular tools generated in this project will provide a strong foundation for future studies linking defects in selenoprotein activity in humans to genetic mutations or polymorphisms in genes that encode components of the Sec incorporation pathway. Selenium, an essential mineral in the diet, is critical for human health. Low dietary intake of selenium, which occurs in many regions of the world, is associated with an increased risk of disease, including thyroid problems, heart disease, inflammation, arthritis, viral infection, and cancer. The goal of this project is to understand how selenium is incorporated into a small but important group of proteins, which play critical roles in the cell and are likely responsible for the beneficial effects of this essential trace element. )
Keywords: 3` Untranslated Regions; Active Sites; Affect; Affinity; Amino Acids; Antioxidants; Arthritis; base; Binding (Molecular Function); Binding Proteins; Binding Sites; Cells; Charge; Cis-Acting Sequence; Complex; Defect; Development; Diet; Dietary intake; disorder risk; Dissociation; DNA Insertion Elements; Elements; Elongation Factor; Endogenous Factors; Enzymes; Eukaryota; Event; Foundations; Future; Gene Mutation; Genes; Genetic Polymorphism; Goals; Health; Health Benefit; Heart Diseases; hormone metabolism; Human; Hypothyroidism; In Vitro; in vivo; Indium; Infection; Inflammation; IS Elements; Knock-in Mouse; Knockout Mice; Knowledge; Learning; Link; Malignant Neoplasms; Mammalian Cell; Maps; Messenger RNA; Micronutrients; Minerals; Modeling; Molecular; Mutagenesis; mutant; novel; Null Lymphocytes; Nutritional Requirements; Organism; Oxidation-Reduction; Pathway interactions; Physiological; Play; Point Mutation; polypeptide; prevent; Process; Protein Binding; Protein Biosynthesis; protein complex; protein function; Proteins; public health relevance; Reading; Recruitment Activity; Research; ribosomal protein L30; Ribosomal Proteins; Ribosomes; RNA; RNA Recognition Motif; RNA-Binding Proteins; Role; Selenium; Selenocysteine; selenocysteine insertion sequence binding protein 2; selenoprotein; Series; Signal Transduction; Site; Specificity; stem; Structure; Terminator Codon; Testing; Thyroid Gland; Thyroid Hormones; Tissues; tool; Trace Elements; Trans-Activators; Translations; Vial device; Virus Diseases; Yeasts
Relevance: NARRATIVE Selenium, an essential mineral in the diet, is critical for human health. Low dietary intake of selenium, which occurs in many regions of the world, is associated with an increased risk of disease, including thyroid problems, heart disease, inflammation, arthritis, vial infection, and cancer. The goal of this project is to understand how selenium is incorporated into a small but important group of proteins, which play critical roles in the cell and are likely responsible for the beneficial effects of this essential trace element. )
Project start date: 2010-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01DK085391-02 (2011): $338060
REGULATION OF SELENOPROTEIN SYNTHESIS BY SECIS-BINDING PROTEINS
M Donna, Professor
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 2R01DK078591-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Selenium is an essential micronutrient that exerts many important health benefits. The element is incorporated into selenoproteins as selenocysteine (Sec). The mammalian selenoproteins perform critical functions in anti-oxidant defense, thyroid hormone metabolism, male reproduction, and development. Sec is encoded by UGA, which is normally read as a stop codon. The recoding of UGA as Sec requires the Sec Insertion Sequence (SECIS) element in the selenoprotein mRNA. Although much progress has been made in understanding the mechanism of Sec incorporation, much less is known about the regulation of this pathway. In selenium deficiency, certain selenoproteins that are critical for health and development are expressed while other ssential selenoproteins are lost. The central hypothesis of our proposal is that this complex hierarchy of selenoprotein expression is maintained by the interplay between multiple trans-acting factors that bind selectively to different SECIS elements. We discovered two new SECIS-binding proteins, nucleolin and eukaryotic initiation factor 4a3 (eIF4a3) that play opposing roles in selectively modulating selenoprotein synthesis. We showed that eIF4a3 links selenium status with differential selenoprotein expression. EIF4a3 is upregulated in selenium-deficient cells where it selectively inhibits the incorporation of Sec into two selenoproteins that perform ssential functions. In preliminary studies, we identified new targets of eIF4a3 and developed a model of the eIF4a3 SECIS interaction. We also present evidence that hnRNP K binds selectively to a SECIS from a ssential selenoprotein but not from an essential selenoprotein. In this project, we will elucidate the roles of eIF4a3 and hnRNP K in regulating the expression of the selenoproteome using a combination of in vitro assays, cell culture systems, and mouse models. The successful completion of this project will provide critical insight into how mammalian cells prioritize the utilization of selenium during selenium insufficiency, an important health problem in many parts of the world. By identifying these regulatory pathways, our studies will provide a strong foundation for developing more specific and targeted approaches for modulating selenoprotein expression in vivo. Selenium is critical for human health. Low dietary intake of selenium, which occurs in many parts of the world, is associated with an increased risk of disease, including thyroid problems, heart disease, arthritis, viral infection, and cancer. The goal of this project is to understand how selenium regulates the synthesis of a small but important group of proteins, which are likely responsible for selenium´s beneficial effects
Keywords: 3` Untranslated Regions; Amino Acids; Anabolism; Antioxidants; Arthritis; Atherosclerosis; base; Beryllium; Binding (Molecular Function); Binding Proteins; Binding Sites; cancer prevention; Cell Culture System; Cells; Cis-Acting Sequence; cohort; Complex; Development; Dietary intake; disorder risk; DNA Insertion Elements; Ensure; Eukaryotic Initiation Factors; Fertility; Foundations; Funding; Genetic Translation; Goals; Health; Health Benefit; Heart Diseases; Heterogeneous-Nuclear Ribonucleoprotein K; hormone metabolism; Human; Immunity; in vitro Assay; in vivo; insight; IS Elements; Lead; Link; male; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Messenger RNA; Micronutrients; Modeling; Molecular; Molecular Profiling; mouse model; novel therapeutics; nucleolin; Outcome; Pathway interactions; Play; Proteins; Reading; Regulation; Regulatory Pathway; Regulon; Reproduction; research study; response; Response Elements; RNA; Role; Selenium; selenium deficiency; Selenocysteine; selenoprotein; Small Interfering RNA; stem; Structure; Terminator Codon; Testing; Thyroid Gland; Thyroid Hormones; Trace Elements; Trans-Activators; Translational Regulation; Translational Repression; Translations; Up-Regulation (Physiology); Virus Diseases; Work
Relevance: Selenium is critical for human health. Low dietary intake of selenium, which occurs in many parts of the world, is associated with an increased risk of disease, including thyroid problems, heart disease, arthritis, viral infection, and cancer. The goal of this project is to understand how selenium regulates the synthesis of a small but important group of proteins, which are likely responsible for selenium´s beneficial effects
Project start date: 2007-07-11
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
2R01DK078591-05 (2011): $392500
NEUROLOGICAL SCIENCES ACADEMIC DEVELOPMENT AWARD (NSADA) (K12)
M Donna, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5K12NS001692-13 from National Institute Of Neurological Disorders And Stroke
Abstract: Project Summary It is the goal of this competing renewal application for the Neurological Sciences Academic Development Award that we continue to train, with the highest rigor, candidates who will succeed in academic child neurology. At UCSF, we have created a program that fosters clinical excellence and rigorous postgraduate scientific training. The NSADA has provided the foundation for our division to grow academically and has allowed us to merge clinical training with scientific discovery. The overall theme of our application is "Translating discoveries in neurological diseases of infancy and childhood". We will offer rigorous basic and translational scientific training to young investigators skilled at recognizing the phenotypes of complex childhood neurological diseases. Our specific aims are to continue to offer a structured program for training academic child neurologists for a career in translational research; to foster career development; and to expose candidates to the intellectual environment of UCSF. Our first candidate will perform an evaluation of the phosphoinositide 3´-kinase signaling pathway in pediatric malignant gliomas by setting up in vitro and in vivo xenograft models from pediatric brain tumors. She will use the facilities of the Brain Tumor Research Center and the mentorship of Dr. Daphne Haas-Kogan and Dr. William Weiss, experts in the field. Additional candidates have been identified who will, upon completion of their clinical training, will submit protocols for review by the internal and external advisory committees. We have included in the grant the rich resources that are provided to these applicants. With well established, nationally recognized and supported training programs to support the didactic phase, coupled with a team of research scientists committed to the career development of child neurologists, we will succeed in bringing forth the next generation of leaders in academic child neurology. It is necessary to adequately train the next generation of leaders in child neurology so that the future care of children with neurological disease can be addressed and improved
Keywords: Academic Training; Address; Advisory Committees; Award; Brain Neoplasms; career; career development; Child; Child Care; Childhood; Childhood Brain Neoplasm; Clinical; Clinical Oncology Supplement (K12); Commit; Complex; Coupled; Daphne plant; Development; Environment; Evaluation; Fostering; Foundations; Future; Goals; Grant; improved; In Vitro; in vivo; infancy; Malignant Glioma; Mentorship; nervous system disorder; Neurologic; Neurologist; next generation; Pediatric Neurology; Phase; Phenotype; Phosphatidylinositols; Phosphotransferases; programs; Protocols documentation; public health relevance; Research; Research Personnel; Resources; Science; Scientist; Signal Pathway; Structure; Training; Training Programs; Translating; Translational Research; Xenograft Model
Project start date: 1993-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-08-197
5K12NS001692-13 (2011): $413995
OXIDANT MECHANISMS IN NEONATAL BRAIN INJURY
M Donna, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R01NS033997-14 from National Institute Of Neurological Disorders And Stroke
Abstract: Oxidative stress is a critical mediator of the injury response after neonatal hypoxia ischemia. Evidence suggests that hydrogen peroxide toxicity is related to cell death but a paradox exists such that H2O2 may also be a signaling molecule that is involved in neuroprotection. In particular, H2O2 may be a critical mediator of hypoxic or ischemic preconditioning in the immature brain. We hypothesize that H2O2 serves as a critical signaling molecule for activation of hypoxia inducible factor 1 (HIF1) to promote protection in the brain after neonatal ischemia. To address this hypothesis we will determine the mechanisms by which HIF1 is regulated by H2O2 to generate a cytoprotective response in immature primary neurons from hippocampus and cortex by measuring HIF 1a induction by mRNA and protein levels, DMA binding activity by EMSA and promoter activity. We will measure HIF1a dependent cytoprotective genes and compare to changes in pro- apoptotic genes and their protein targets. We will measure H2O2 and the cellular localization of reactive oxygen species and we will block preconditioning using antisense or knockdown strategies against HIF1. We will study redox-sensitive signaling pathways such as MARK, PI3K/Akt to determine their involvement in hypoxic HIF1 signaling and neuronal protection. We will assess phosphorylation states and use pharmacological inhibitors to determine relevant activities. The second aim will test how altering glutathione peroxidase activities by overexpression or knockdown will affect hypoxic preconditioning and injury in vitro and in vivo and how this relates to H1F1 activation and redox signaling. We will measure HIF1 activation and H2O2 levels necessary to achieve preconditioning neuroprotection. In the final aim we will determine how modulation of HIF1 activity by genetic deletion, pharmacological stabilization or induction by growth factors affect hypoxic preconditioning and neuronal injury in vivo. We will also test behavioral outcomes in these animals to determine whether this is a functional deficit. RELEVANCE TO PUBLIC HEALTH. Lack of oxygen to the newborn brain is the major cause of lifelong disability in children resulting in mental retardation, epilepsy and cerebral palsy. Understanding pathways for protecting the brain will result in therapeutic avenues for brain recovery
Keywords: 0-11 years old; 0-6 weeks old; 21+ years old; Acquired brain injury; Active Oxygen; Address; Adult; adult human (21+); Affect; Age; Ammon Horn; Animals; Apoptotic; balance; balance function; behavior test; behavioral test; Binding; Binding (Molecular Function); Biological Preservation; biological signal transduction; Blood flow; Blood Vessels; Blotting, Western; Brain; brain damage; Brain Hypoxia-Ischemia; Brain Injuries; brain lesion (from injury); brain volume; Cell Communication and Signaling; Cell Death; Cell Signaling; Cells; Cerebral Palsy; Child; Child Youth; children; Children (0-21); Cornu Ammonis; D-Glucose; Dextrose; disability; ECSF; electron acceptor; EMSA; Encephalon; Encephalons; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Relaxing Factor; epilepsia; Epilepsy; Epileptic Seizures; Epileptics; epileptiform; epileptogenic; Epoetin; Equilibrium; erythrocyte colony stimulating factor; Erythropoietin; experiment; experimental research; experimental study; Extracellular Signal-Regulated Kinase Gene; Gel; Gene Expression; gene product; Gene Targeting; Gene Transcription; Generalized Growth; Genes; Genetic; Genetic Transcription; GFAC; Glucose; glutathione peroxidase; Glutathione[{..}]hydrogen-peroxide oxidoreductase; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; H2O2; Health; hematopoietin; HIF 1; HIF-1 protein; HIF1; HIF1 protein; hippocampal; Hippocampus; Hippocampus (Brain); Human, Adult; Human, Child; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Hypoxia; hypoxia inducible factor 1; hypoxia ischemia; Hypoxia-Ischemia, Brain; Hypoxic; hypoxic ischemic encephalopathy; Immunologic, Luciferase; In Vitro; in vivo; Infant, Newborn; inhibitor; inhibitor/antagonist; Injury; injury response; Intermediary Metabolism; Intracellular Communication and Signaling; Investigators; Ischemia; Ischemic Preconditioning; kinase inhibitor; knock-down; Literature; Luciferases; MAP Kinase Gene; MAPK; Measures; Mediator; Mediator of Activation; Mediator of activation protein; Mental Retardation; Messenger RNA; Metabolic Processes; Metabolism; METBL; Mitogen-Activated Protein Kinase Gene; Molecular Interaction; Mononitrogen Monoxide; mRNA; necrocytosis; Necrosis; Necrotic; Neonatal; Neonatal Brain Injury; neonatal hypoxia-ischemia; neonatal hypoxic-ischemic brain injury; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; neuron injury; neuronal; Neuronal Injury; Neurons; neuroprotection; newborn human (0-6 weeks); Newborn Infant; Newborns; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; O element; O2 element; ontogeny; Outcome; overexpression; Oxidants; oxidation reduction reaction; Oxidation-Reduction; Oxidative Stress; Oxidizing Agents; Oxygen; Oxygen Deficiency; Oxygen Radicals; pathway; Pathway interactions; Peptidyl Prolyl Hydroxylase; Phosphorylation; preconditioning; Preconditionings, Ischemic; preservation; Preservation, Biologic; Preservation, Biological; Pro-Oxidants; Process; Procollagen Prolyl 4-Hydroxylase; Procollagen-L-proline, 2-oxoglutarate[{..}]oxygen oxidoreductase; Procollagen-Proline Dioxygenase; Production; programs; Programs (PT); Programs [Publication Type]; Proline Hydroxylase; Proline, 2-Oxoglutarate 4-Dioxygenase; Prolyl 4-Hydroxylase; Prolyl Hydroxylase; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); protein blotting; Protein Phosphorylation; Proteins; Protocollagen Prolyl Hydroxylase; Reactive Oxygen Species; Recovery; Redox; Regulation; repair; repaired; Research Personnel; research study; Researchers; response; response to injury; RNA Expression; RNA, Messenger; RNA, Small Interfering; Role; Running; Seizure Disorder; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; Signaling Molecule; siRNA; Small Interfering RNA; social role; Targetings, Gene; Testing; Therapeutic; Time; Tissue Growth; Toxic effect; Toxicities; Trans-Activation (Genetics); Transactivation; Transcription; Transcription, Genetic; trend; Up-Regulation; Up-Regulation (Physiology); Upregulation; vascular; Vascular Endothelial Growth Factors; Vegf; VEGFs; Western Blotting; Western Blottings; Western Immunoblotting; Work; youngster
Project start date: 1996-04-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5R01NS033997-14 (2011): $276090
Sponsored Links Excellgen http://Excellgen.com
ADHERENCE TO THE HCT MEDICAL REGIMEN: INFLUENCE OF CANCER PATIENT-CARGIVER DYADS
M Donna, Assistant Professor
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 1K23CA149082-01A1 from National Cancer Institute
Abstract: Dr. Donna Posluszny´s career goal is to develop an independent research program focused on designing and evaluating novel behavioral and psychosocial interventions to enhance cancer patient-family caregiver dyads´ ability to adhere to complex medical regimens and improve patient physical health outcomes. The K23 award will enable Dr. Posluszny, who is an Assistant Professor of Medicine and a clinical psychologist, to take the necessary first steps towards this goal by providing training in medical regimen research in cancer; behavioral and psychosocial intervention development in the field of adherence research in cancer; and methodologies for conducting and analyzing longitudinal and interventional clinical research with patient and family caregiver dyads. Specifically, the five-yer training plan includes (1) formal coursework; (2) regular mentoring from mentors and consultants; (3) participation in seminars, workshops, and national conferences; (4) mentored research; and (5) clinical practice. The combination of Dr. Posluszny´s clinical training, the expertise of her mentoring team, and the research environment of the University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute will facilitate the successful implementation of the proposed training plan and research study. The research plan is devoted to the implementation of an independent project to evaluate patient and family caregiver adherence to the complex, multicomponent post- hematopoietic stem cell transplantation (HCT) during the first 100 days post HCT and the development and piloting of a patient-caregiver dyad-focused psychoeducational intervention, grounded in the principles of Problem-Solving Therapy, to enhance adherence to the post-HCT medical regimen. Specific aims are (1) investigation of how patients and caregivers divide the responsibilities associated with adherence to the multicomponent post-HCT medical regimen post-hospital discharge; (2) determination of rates of, key risk factors for, and patient health outcomes associated with nonadherence to the post-HCT medical regimen; and (3) development and preliminary evaluation of a pilot patient-caregiver dyad-focused psychoeducational intervention designed to decrease nonadherence to the post-HCT medical regimen. This application addresses the National Cancer Institute´s continuing commitment to developing initiatives to understand the role of family in the cancer experience and improve patient health outcomes, and is unique in its dyadic focus on adherence. Collectively, the outcomes of this study will foster the identification of both adaptive and nonadaptive dyadic approaches to adherence to the post-HCT medical regimen and provide the groundwork and preliminary data for a psychoeducational intervention to improve adherence for HCT patients and their family caregivers, and thereby improve patient health outcomes
Keywords: Address; Adherence (attribute); Affect; Allogenic; arm; Attention; base; Behavior; Behavioral; Blood; Bone Marrow Transplantation; Cancer Patient; career; Caregivers; Caring; Catheters; Cell Transplantation; Characteristics; Clinical; clinical practice; Clinical Research; Complex; coping; Data; Deltastab; design; Development; Diet; Disease; Educational workshop; Enrollment; Ensure; Environment; Evaluation; evidence base; experience; Family; Family Caregiver; Fostering; Goals; Graft Rejection; Graft-vs-Host Disease; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hospitals; Immunocompromised Host; improved; international center; Intervention; Investigation; Life; Malignant Neoplasms; Mediating; Medical; medical appointment; medical complication; medical schools; Medicine; meetings; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Monitor; National Cancer Institute; novel; Opportunistic Infections; Outcome; Outcome Study; Patient Discharge; patient population; Patients; Perception; Persons; Pharmaceutical Preparations; physical conditioning; Population; Problem Solving; problem solving therapy; Procedures; professor; programs; prospective; psychoeducational intervention; psychological distress; Psychologist; psychosocial; Randomized; Randomized Clinical Trials; Regimen; Reporting; Research; research study; Risk; Risk Factors; Role; satisfaction; Schedule; skills; social; Subgroup; success; symposium; Testing; therapy design; therapy development; Training; Transplantation; Treatment outcome; Universities; University of Pittsburgh Cancer Institute; Work
Relevance: Hematopoietic stem cell transplantation (HCT) is an increasingly prevalent lifesaving treatment option for hematologic cancer patients, with an estimated 25,000 procedures performed annually worldwide (Center for International Blood and Marrow Transplantation Research; 2010). After HCT, patients and their family caregivers must work together to adhere to the complex post-HCT medical regimen, which is critical for good patient health outcomes. The proposed work will allow us to identify adaptive and nonadaptive patient- caregiver approaches to positive adherence to the post-HCT medical regimen, providing a focus for development and preliminary evaluation of a brief psychoeducational intervention to help patients and family caregivers better adhere to the regimen, and thus, improve patient health outcomes
Project start date: 2011-09-20
Project end date: 2016-08-31
Budget start date: 20-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-10-060
1K23CA149082-01A1 (2011): $106276
EMPLOYMENT INTERVENTION FOR OFFENDERS
M Donna, Research Asst Prof
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01DA019600-05 from National Institute On Drug Abuse
Abstract: Crime and unemployment represent the most significant cost of drug abuse. Offenders who are employed are less likely to relapse and commit fewer crimes. Despite these findings, employment programs are only viewed as ancillary treatment for drug abuse and specific employment interventions targeting offenders are limited, and those that are available suffer from a number of methodological flaws. Preliminary work at our Center has shown the importance of integrating drug and employment counseling with methadone clients. This integrated counseling and employment (ICE) intervention is a manualized treatment based on interpersonal cognitive problem solving theory that has been developed under a NIDA funded behavioral therapies development grant. Integrating employment services into drug therapy sessions could be a more effective, less costly and more functional alternative than the traditional approach of making referrals for employment services. The current study proposes to implement the ICE intervention with criminal justice clients who are mandated to drug treatment. Many offenders need employment services and often are required as part of their parole to work. Parolees will be randomly assigned to receive either the integrated counseling and employment (ICE) intervention (n=100) or a drug counseling only control condition (n=100). There are two specific aims of the proposed study The first aim is to evaluate the effectiveness of the ICE intervention among offenders over an 18 month period post-treatment entry in terms of the primary outcomes of during treatment employment, drug use, and crime including parole infractions; and the secondary outcomes of HIV risk behaviors, post-treatment employment, drug use and crime, and other areas of functioning (e.g., psychiatric, social/family functioning). The second aim is to perform a benefit-cost analysis comparing the integrated treatment with the drug counseling only control condition. Providing offenders with integrated drug and employment counseling may help reduce recidivism and improve employment prospects for this group, thus reducing the large societal cost of drug abuse
Keywords: addiction; Address; Aftercare; American; Area; Attention; base; Behavior Therapy; career; Caring; Chronic; Client; Cognitive; Commit; Control Groups; cost; Cost-Benefit Analysis; Costs and Benefits; Counseling; Crime; Criminal Justice; Data; design; Drug abuse; Drug Addiction; Drug usage; Educational process of instructing; Effectiveness; Effectiveness of Interventions; Employment; Enrollment; Evolution; experience; Family; follow-up; Forensic Medicine; Funding; Future; Goals; Grant; HIV; Imprisonment; improved; Intervention; Investigation; Jail; Joints; Lead; Length of Stay; Life; Manuals; Medicine; meetings; member; Methadone; methadone maintenance; Motivation; Naltrexone; National Institute of Drug Abuse; National Research Council (U.S.); Occupations; offender; Opiates; Outcome; Outpatients; parole; parolee; Pharmaceutical Preparations; Pharmacotherapy; Phase; Philadelphia; Preclinical Drug Evaluation; primary outcome; Problem Solving; Professional counselor; programs; Randomized; Randomized Controlled Trials; recidivism; Recovery; Recruitment Activity; Relapse; Research; Research Design; Research Personnel; Risk Behaviors; secondary outcome; Services; skills; skills training; social; Societies; Study Subject; Substance abuse problem; substance abuse treatment; Substance Addiction; success; Supported Employment; theories; therapy development; Time; treatment program; Trust; Unemployment; Work
Project start date: 2006-09-04
Project end date: 2012-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2012
5R01DA019600-05 (2010): $317151
IN VIVO TESTING AND STATISTICS CORE
M Donna
Stanford Universitycity: Stanford country: United States (us)
Abstract: Core B has four goals ¿ The first goal is to perform bioluminescent imaging of luciferase. ¿ The second goal is to help coordinate, supervise and oversee all animal studies for all five projects and to conduct all of the normal tissue toxicology testing where required. ¿ The third goal of the project is to provide a centralized cell line, medium and serum bank to ensure uniformity as much as possible between the test systems used by all of the projects. The Core will also perform the serum testing and mycoplasma testing of the cell lines used by all the projects. ¿ The fourth goal is to provide statistical support for all of the projects in the Program Project
Keywords: Animals; Blood Serum; cancer metastasis; Cell Line; Cell Lines, Strains; CellLine; Cells; Clinical; cultured cell line; Drug Combinations; drug detection; drug testing; Ensure; Eperythrozoon; Goals; Haemobartonella; Hypoxia; Hypoxic; Image; imaging; Immunologic, Luciferase; in vivo; Luciferases; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Molecular; Mycoplasma; Neoplasm Metastasis; Normal Tissue; Normal tissue morphology; Oxygen Deficiency; programs; Programs (PT); Programs [Publication Type]; Science of Statistics; Secondary Neoplasm; Secondary Tumor; Serum; Source; Statistics; statistics; System; System, LOINC Axis 4; Testing; Toxic effect; Toxicities; Toxicity Testing; Toxicity Tests; Toxicology; tumor; Tumor Cell Migration
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5P01CA067166-15_9002 (2011): $156504
OPIOID RECEPTOR POLYMORPHISMS AND NONHUMAN PRIMATE MODELS OF ALCOHOL ABUSE
M Donna
Harvard University (medical School)city: Boston country: United States (us)
Grant 5R01AA016828-03 from National Institute On Alcohol Abuse And Alcoholism
Abstract: Alcohol abuse and alcoholism are widespread public health problems that are associated with debilitating medical, social, and psychological consequences. The opioid antagonist naltrexone is approved for the treatment of alcohol dependence; however, naltrexone is not universally effective in all people. Recent evidence suggests that a N40D (A188G) single nucleotide polymorphism (SNP) in the human mu opioid receptor gene may contribute to individual variation in sensitivity to the behavioral effects of alcohol, as well as to subsequent responsiveness to naltrexone therapy. Rhesus monkeys also have a SNP (P26R, C77G) that appears to have many of the same functional, physiological and behavioral consequences as the human SNP. Using state-of-the-art genotyping techniques and in vitro assays, allelic variants of the rhesus monkey mu opioid receptor that alter protein structure and/or function or affect subsequent gene expression levels will be systematically identified and characterized (Specific Aim 1). In addition, the role of mu opioid receptor haplotypes in individual sensitivity to the reinforcing and relapse-inducing effects of alcohol will be explored in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self-administer alcohol (Specific Aim 2). Finally, the role of mu opioid receptor haplotypes in individual responsiveness to the ability of naltrexone to reduce oral alcohol self-administration and diminish alcohol priming-induced reinstatement will be investigated in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self- administer alcohol (Specific Aim 3). Integration of results from the three specific aims will yield needed information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, the results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual´s likelihood of positive treatment outcome. Alcohol use disorders are widespread public health problems that are associated with debilitating medical, social, and psychological consequences and for which no universally effective treatment medication is available. Our studies will yield key information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, our results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual´s likelihood of positive treatment response
Keywords: Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; alcohol effect; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; Alcoholism; alcoholism therapy; Alcohols; base; Behavioral; brain tissue; Code; effective therapy; Effectiveness; Gene Expression; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Health; Human; In Vitro; in vitro Assay; Individual; Individual Differences; Macaca mulatta; Maintenance; Medical; Modeling; mRNA Expression; Naltrexone; Narcotic Antagonists; neurogenetics; nonhuman primate; novel strategies; Opioid; Opioid Receptor; Oral; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Pharmacotherapy; Physiological; Play; Procedures; protein structure; Proteins; psychologic; public health medicine (field); receptor; Receptor Gene; Receptors, Opioid, mu; Relapse; Research; response; Role; Self Administration; Self-Administered; Single Nucleotide Polymorphism; social; Techniques; Therapeutic; Training; Treatment Efficacy; Treatment outcome; treatment response; Untranslated Regions; Variant; Variation (Genetics)
Relevance: Alcohol use disorders are widespread public health problems that are associated with debilitating medical, social, and psychological consequences and for which no universally effective treatment medication is available. Our studies will yield key information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, our results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual´s likelihood of positive treatment response
Project start date: 2009-09-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01AA016828-03 (2011): $392113