The Role of a Specific Epigenetic Mechanism in Cocaine-induced Drug-seeking Behav

特定表观遗传机制在可卡因诱导的药物寻求行为中的作用

基本信息

批准号：
8464538
负责人：
GEORGE A ROGGE
金额：
$ 5.39万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2014-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464538
关键词：
Academia Animals Biochemical Biological Assay Brain Cell Nucleus Chromatin Cocaine Collaborations Complement Complex DNA Data Analyses Dependovirus Drug Addiction Enzymes Epigenetic Process Ethics Future Gene Expression Gene Expression Regulation Genetic Transcription HDAC1 gene HDAC2 gene HDAC4 gene HDAC6 gene Hippocampus (Brain)Histone Acetylation Histone Deacetylation Histones Immunohistochemistry In Vitro Intake Investigation Knock-in Mouse Laboratories Laboratory Scientists Lead Learning Lentivirus Vector Lysine Measures Memory Mentors Molecular Mus Mutate Neurologic Nuclear Nucleus Accumbens Personal Satisfaction Pharmaceutical Preparations Pharmacotherapy Phase Philosophy Postdoctoral Fellow Principal Investigator Protein Isoforms Proteins Psyche structure Relative (related person)Research Research Personnel Research Proposals Research Training Rewards Role Self Administration Sirtuins Site Sodium Butyrate Synaptic plasticity Techniques Testing Training Training Programs Transcriptional Activation Vorinostat Western Blotting addiction behavioral pharmacology career chromatin modification design drug seeking behavior graduate student histone acetyltransferase histone deacetylase 3 in vitro activity in vivo inhibitor/antagonist long term memory memory process neurochemistry novel preference prevent professor protein complex recombinase research study response responsible research conduct skills undergraduate student valproate

项目摘要

DESCRIPTION (provided by applicant): The focus of this research proposal is to examine the role of histone deacetylase 3 (HDAC3) in vivo as a potential negative regulator of context-drug associated memory formation. Previous studies have shown that HDAC3 forms multi-protein complexes with HDACs 4 and 5 in vitro, via interactions with NCoR1 and 14-3-3 protein, respectively. We hypothesize that HDAC3 associates with HDACs 4 and/or 5 in vivo, in the hippocampus and nucleus accumbens (NAc), to translocate to the nucleus and deacetylates histones, repressing transcription necessary for long-term contextual memory formation associated with the acquisition of cocaine-induced conditioned place preference (CPP). Understanding the HDAC isoforms involved in context-drug associated memory formation will contribute to an understanding of the molecular mechanisms of long-term memory formation and drug-seeking behaviors and may eventually lead to selective pharmacotherapies which target chromatin modifying enzymes to treat drug addiction. Specific Aim 1. To examine the effects of Hdac3 deletion on the expression of other HDACs and histone acetylation. Hypothesis: HDAC3 forms a complex with HDAC4 and 5 in vivo to facilitate nuclear localization and histone deacetylation. Specific Aim 2. To examine the role of HDAC3 in acquisition of cocaine-induced CPP. Hypothesis: Loss of HDAC3 function will significantly facilitate the acquisition of cocaine-induced CPP. Specific Aim 3. To examine whether HDAC3 serves as a critical negative regulator of cocaine- induced CPP acquisition. Hypothesis: Over-expression of HDAC3 and/or NCoR1 will prevent acquisition of cocaine-induced CPP. The research training program will be designed: 1) for the applicant to be trained in behavioral pharmacology techniques, allowing him to effectively study epigenetic mechanisms of context-drug associated memory formation; 2) to train the applicant to be an independent investigator so he may be proficient in the future as a laboratory scientist, mentor and lead investigator in academia; and 3) to emphasize responsible conduct of research, including the humane treatment of animals used in laboratory experiments and ethical data analysis, mentoring of graduate and undergraduate students, building collaborations with other post- doctoral fellows and principal investigators and proficient design and execution of experiments. Those skills will allow the applicant to carry on independent investigations of his own during the next phase of his career as an academic research professor.

描述（由申请人提供）：本研究计划的重点是检查组蛋白脱乙酰酶 3 (HDAC3) 在体内作为背景药物相关记忆形成的潜在负调节剂的作用。先前的研究表明，HDAC3 分别通过与 NCoR1 和 14-3-3 蛋白相互作用，在体外与 HDAC 4 和 5 形成多蛋白复合物。我们假设 HDAC3 在体内海马体和伏隔核 (NAc) 中与 HDAC 4 和/或 5 相关联，易位到细胞核并使组蛋白脱乙酰化，抑制与可卡因获取相关的长期情境记忆形成所必需的转录-诱发条件性位置偏好（CPP）。了解参与背景药物相关记忆形成的 HDAC 亚型将有助于理解长期记忆形成和药物寻求行为的分子机制，并可能最终导致针对染色质修饰酶来治疗药物成瘾的选择性药物疗法。具体目的 1. 检测Hdac3缺失对其他HDAC表达和组蛋白乙酰化的影响。假设：HDAC3 在体内与 HDAC4 和 5 形成复合物，以促进核定位和组蛋白脱乙酰化。具体目标 2. 检查 HDAC3 在可卡因诱导的 CPP 获得中的作用。假设：HDAC3 功能的丧失将显着促进可卡因诱导的 CPP 的获得。具体目标 3. 检查 HDAC3 是否作为可卡因诱导的 CPP 获得的关键负调节因子。假设：HDAC3 和/或 NCoR1 的过度表达将阻止可卡因诱导的 CPP 的获得。研究培训计划将设计为：1）为申请人提供行为药理学技术培训，使他能够有效地研究背景药物相关记忆形成的表观遗传机制； 2) 培训申请人成为一名独立研究者，以便他将来能够成为学术界的实验室科学家、导师和首席研究员； 3) 强调负责任的研究行为，包括人道地对待实验室实验和道德数据分析中使用的动物、指导研究生和本科生、与其他博士后研究员和主要研究人员建立合作以及熟练地设计和执行实验。这些技能将使申请人能够在其作为学术研究教授的职业生涯的下一阶段进行自己的独立调查。