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Novel Role for Sirtuin Signaling Mechanisms and Downstream Targets in Depression

Sirtuin 信号机制和下游靶点在抑郁症中的新作用

基本信息

批准号：
9054163
负责人：
Deveroux Ferguson
金额：
$ 23.73万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054163
关键词：
ADP Ribose Transferases Affect Animal Model Antidepressive Agents Anxiety Award Behavior Behavioral Behavioral Assay Binding Biology Brain ChIP-seq Chairperson Chromatin Chronic Chronic stress Data Development Diagnostic tests Disease Drug Addiction Environment Epigenetic Process Exposure to Family Functional disorder Gene Activation Gene Expression Genes Genetic Genetic Transcription Genetically Engineered Mouse Grant HSV vector Histone Deacetylase Individual Infusion procedures Institutes Knowledge Lead Life LoxP-flanked allele Measures Mediating Mental Depression Mentors Mentorship Methodology Modeling Molecular Mood Disorders Morbidity - disease rate Mus Neurobiology Neurons Neurosciences New York Nucleus Accumbens Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Play Population Positioning Attribute Predisposition Prevalence Preventive Intervention Preventive measure Property Proteins Regulation Repression Research Research Personnel Resveratrol Rewards Risk Factors Rodent Model Role Scientist Signal Pathway Signal Transduction Simplexvirus Sirtuins Stress Technology Testing Therapeutic Intervention Time Tissue Sample Tissues Training Transgenic Mice United States National Institutes of Health Viral Vector Work anxiety-like behavior base behavior influence behavioral response brain tissue career cell type chromatin immunoprecipitation depression model depressive symptoms effective therapy experience gene environment interaction gene repression genetic approach genome-wide improved inhibitor/antagonist interest knock-down medical schools member mortality neuropsychiatric disorder next generation sequencing novel osmotic minipump overexpression programs resilience social stress related disorder tenure track therapeutic target tool vector

项目摘要

Project Summary Epigenetic factors may play a key role in unraveling the molecular mechanisms underlying the pathogenesis of several neuropsychiatric disorders, including depression and drug addiction. Genes appear to explain only part of the risk factor for developing these disorders. The NIH Pathway to Independence Award (K99/R00) will significantly facilitate the candidate's ability to begin his career as an independent scientist, allowing him to study the epigenetic mechanisms underlying the gene-environment interactions observed in the onset of major mood disorders. Under the primary mentorship of Dr. Eric Nestler, Chairman of the Department of Neuroscience, and Director of the Friedman Brain Institute, at Mount Sinai School of Medicine in New York, the Pathway to Independence Awards would provide the candidate the opportunity to extend and develop his training and expertise in next generation sequencing technologies and cell type specific signaling analysis. The Award would advance the candidate's long term career objectives to: (1) determine how the environment interacts with genes and identify mechanisms by which experience confers enduring changes in gene expression, and (2) discover novel susceptibility (or resilience) genes to understand how they influence behavior. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is rudimentary. Thus, there is an urgent need to discover novel signaling pathways contributing to the development of depression so that better diagnostic tests, treatments, and preventive measures can be attained. The objectives of this program of research are to evaluate the role of SIRT1 and its downstream targets as potential new candidates for the treatment of neuropsychiatric disorders by performing chromatin immunoprecipitation followed by genome-wide profiling (ChIP-seq) in nucleus accumbens (NAc) tissue from control and socially defeated stressed mice. Preliminary data from our lab show that chronic social defeat stress, an ethologically validated model of depression and other stress-related disorders, modulates SIRT1 levels in the NAc and is a pro-depressant sufficient to increase stress sensitivity. The SIRT1 protein is the founding member of a family of NAD+-dependent deacetylases and ADP-ribosyltransferases, termed sirtuins. In this grant we propose to test the hypothesis that modulation of SIRT1 constitutes a novel candidate therapeutic target for antidepressants. In the mentored K-phase of this grant (Specific Aim 1 and Specific Aim 2) we will directly determine the role of sirtuins in regulating depressive- and anxiety-like behaviors using pharmacological and genetic tools. First, we will inhibit or increase the activity of sirtuins by direct intra-NAc infusion of a pharmacological inhibitior (sirtinol) or activator (resveratrol) to assess the effects of sirtuins on the development of stress-induced depressive and anxiety-like behaviors. Next, we will specifically target SIRT1 using a genetic approach to overexpress HSV-Cre viral vectors in the NAc of floxed SIRT1 (SIRT1flx) mice to knock-down SIRT1 levels, or to increase SIRT1 levels by overexpressing SIRT1 using HSV-SIRT1 vectors in the NAc. In Specific Aim 2 we also will identify transcriptional targets of SIRT1 in the NAc regulated by social defeat and antidepressants in susceptible and resilient mice by performing ChIP-Seq for SIRT1 in addition to markers of gene activation and repression. In the independent phase (R00), Specific Aim 3, will characterize the effects of social defeat on sirtuin signaling in a cell type specific manner in the NAc using drd1-GFP and drd2-GFP transgenic mice, allowing for the identification of striatonigral and striatopallidal medium spiny neurons (MSNs). In summary, the research proposed in this Pathway to Independence Award will prepare the candidate to develop a fully independent research program capable of integrating a wide range of molecular and behavioral approaches in a technically advanced and high impact manner, including: (i) lines of genetically engineered mice to target cell type specific regulation of sirtuin signaling after exposure to chronic stress, (ii) the ability to isolate chromatin from brain tissue, (iii) ChIP followed by genome-wide profiling, (iv) a rodent model of depression with high validity, and (v) automated behavioral assays measuring many depression- and anxiety-like behavioral responses. .

项目总结