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Transcriptional Mechanisms of Drug Addiction

毒瘾的转录机制

基本信息

批准号：
10062498
负责人：
ERIC J. NESTLER
金额：
$ 182.17万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062498
关键词：
Address Affect Animal Model Animals Automobile Driving Autopsy Back Behavioral Bioinformatics Biology Brain Brain region Cell physiology Chromatin Cicatrix Code Collaborations Complex Corpus striatum structure DNA Modification Process Data Data Set Development Dorsal Drug Addiction Drug Exposure Enhancers Exhibits Female Fiber Functional disorder Gene Expression Gene Expression Regulation Gene Proteins Gene Transfer Genes Genetic Transcription Genome Human Individual Investigation Knowledge Learning Link Mediating Mediator of activation protein Methods Microglia Mining Modeling Molecular Mus Mutant Strains Mice Neurobiology Neuroglia Neurons Nucleus Accumbens Opiate Addiction Opioid Pharmaceutical Preparations Photometry Play Prefrontal Cortex Procedures Program Research Project Grants Proteins Psychiatry Psychostimulant dependence Public Health RNA RNA Splicing Recording of previous events Regulation Relapse Research Research Personnel Rest Rewards Rodent Role Self Administration Sex Differences Stimulus Structure Substance Use Disorder Synapses Syndrome Tissues Transcriptional Regulation Untranslated RNA Validation Variant Viral Viral Genes Work Yasmin addiction brain reward regions brain tissue cell type chromatin modification chromatin remodeling circular RNA desensitization drug of abuse gene function genome-wide histone modification interest male multidisciplinary multiple datasets neurophysiology neuropsychiatry novel novel strategies operation optogenetics pre-clinical programs response sex tool transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT– OVERALL PPG This new Program Project Grant (PPG) utilizes recent advances in transcriptional biology to fundamentally increase our knowledge of the long-lasting abnormalities in brain that underlie stimulant and opiate addiction. Our work focuses on several specific cell types in key addiction-related brain regions: nucleus accumbens, dorsal striatum, and prefrontal cortex. The PPG is composed of four Projects and three Cores all at Mount Sinai. The PIs are leaders in their fields who have an established history of effective collaboration and use their complementary expertise and approaches to chart a multidisciplinary course in the proposed research. Project 1 (Eric Nestler) focuses on novel transcription factors induced in brain reward regions by self-administered stimulants and opiates. Project 2 (Paul Kenny) mines the PPG’s complex datasets to understand the role played by circular RNAs in addiction; these are a newly discovered class of non-coding RNAs some of which, within brain, are concentrated at synapses. Project 3 (Anne Schaefer) focuses on the influence of microglia in controlling transcriptional responses to drugs of abuse within brain reward neurons and their behavioral consequences. Project 4 (Yasmin Hurd) concentrates on the influence of enhancer regions, and their transcriptional and chromatin mediators, in controlling molecular and behavioral adaptations to drugs of abuse. All four projects validate findings from animals in human postmortem brain tissue, while discoveries in human substance use disorders are fed back to animal models to explicate the underlying mechanisms involved. The PPG is supported by three Cores, an Administrative Core (Eric Nestler) to oversee and coordinate PPG operations; an Animal Models Core (Vanna Zachariou) to provide animal models of addiction and other advanced tools (e.g., viral gene transfer, inducible mutant mice) to manipulate individual genes of interest in specific cell types of the targeted brain regions and thereby provide causal evidence linking molecular-cellular plasticity to addiction-related phenomena; and a Gene and Chromatin Analysis Core (Li Shen) to provide state- of-the-art methods and bioinformatics to characterize genome-wide regulation of gene expression and chromatin modifications in addiction. This pioneering investigation of transcriptional mechanisms of drug addiction will help drive major advances in the field.

项目摘要/摘要-整体PPG