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

• 批准号: 8256600
• 负责人: GEORGE A ROGGE
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8256600
• 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; Wood material; 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

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. PUBLIC HEALTH RELEVANCE: The philosophy of drug addiction has changed drastically from early misconceptions that addicts are "simply unable to control themselves." It has become clear that the long-term intake of abusive substances fundamentally alters the neurochemistry of an addict such that he/she becomes dependent on the drug for either physical or mental well-being. Thus a complete understanding of the persistent neurological changes underlying drug dependency, such as epigenetic mechanisms of drug-induced alterations in gene expression, may reveal novel and specific pharmacotherapy targets for addiction treatments.

描述(由申请人提供)：这项研究计划的重点是检验组蛋白脱乙酰酶3(HDAC3)在体内作为上下文药物相关记忆形成的潜在负面调节因子的作用。先前的研究表明，HDAC3在体外分别通过与NCoR1和14-3-3蛋白相互作用，与HDAC4和5形成多蛋白复合体。我们假设HDAC3与体内的HDAC4和/或5在海马体和伏隔核(NAC)中结合，移位到细胞核并去乙酰化组蛋白，抑制与可卡因诱导的条件性位置偏爱(CPP)相关的长期语境记忆形成所需的转录。了解参与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找行为的分子机制，并最终可能导致针对染色质修饰酶的选择性药物疗法来治疗药物成瘾。具体目的1.检测HDAC3缺失对其他HDACs表达和组蛋白乙酰化的影响。假设：HDAC3在体内与HDAC4和5形成复合体，促进核定位和组蛋白去乙酰化。具体目的2.研究HDAC3在可卡因诱导的CPP形成中的作用。假设：HDAC3功能的丧失将显著促进可卡因诱导的CPP的获得。具体目的3.研究HDAC3是否作为可卡因诱导的CPP获得的关键负性调节因子。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)对申请者进行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学机制；2)培训申请者成为一名独立研究员，以便他将来可以熟练地成为学术界的实验室科学家、导师和首席研究员；以及3)强调负责任的研究行为，包括人道地对待用于实验室实验和伦理数据分析的动物，指导研究生和本科生，与其他博士后研究员和首席研究员建立合作，以及熟练地设计和执行实验。这些技能将使申请者能够在其学术研究教授职业生涯的下一阶段进行自己的独立调查。 与公共健康相关：吸毒成瘾的哲学已经从早期的错误观念发生了巨大的变化，人们认为吸毒者“只是无法控制自己”。很明显，长期摄入虐待物质从根本上改变了成瘾者的神经化学，使他/她变得依赖药物以获得身体或精神上的健康。因此，完全了解药物依赖背后的持续性神经变化，如药物诱导的基因表达变化的表观遗传学机制，可能会揭示药物成瘾治疗的新的和特定的药物治疗靶点。