Epigenetic Status of MAOA Gene as a Module of Translational Behavioral Research

描述(由申请人提供)：本申请描述了一个系统的5年培训计划，旨在启动神经科学的独立研究生涯，重点是功能表观遗传学和脑成像。候选人的总体目标有助于理解大脑功能潜在的生物机制，特别是更好地了解个体变异在遗传和表观遗传构成中的作用。为了实现这一目标，我们制定了严格的培训计划，整合了针对候选人的目标、技能和经验量身定做的教学和研究部分。布鲁克海文国家实验室(BNL)为完成这一培训提供了IC环境--它是最先进的功能神经成像技术的发源地。该项目的导师是各自领域的杰出科学家和杰出专家。建议的研究项目实施了实现这一目标的实际手段。它的目的是研究(该提案的重点是单胺氧化酶A(MAOA)基因)影响大脑功能的机制。这项研究将利用BNL提供的独特机会：正电子发射断层扫描仪能够直接测量活着的人脑中MAOA的活动。PET数据将在高分辨率表观遗传学分析中得到补充。本研究的总体目标是研究脑化学中表观遗传机制的个体差异对脑化学的贡献，以了解不同行为表型背后的神经生物学基础。我们假设，表观遗传机制在MAOA基因的转录调控中发挥着重要作用，这可能有助于人类行为的变化。为了测试这一点，我们建议询问基因甲基化，并确定一组正常个体的甲基化变异。次级个体的甲基化模式将与他们的脑成像数据联系起来，测量MAO A活动数据的数量(用于确定MAOA基因的甲基化与大脑中的氨基酸之间是否存在相关性)。这项研究将通过解决脑科学中一个关键的悬而未决的问题来增加新的信息：什么和生化底物是人类行为的基础？经过验证的表观遗传调控知识提高了我们对基因和环境之间相互作用的一般理解，从而增加了一门新的INS脑生物学。该项目的主要目标是为候选人提供必要的培训，以便在神经科学领域开始独立的职业生涯，特别是在神经成像和表观遗传学方面。为了实现这一目标，学员将获得有价值的科学数据，并对我们理解调节脑神经化学的机制做出重大贡献，从而为越来越多关于MAOA基因、环境应激源和行为之间关系的报告增加生化相关性。在这份K01申请中，候选人提出了一个大脑成像和遗传学的培训计划，以帮助STU影响与奖励、唤醒和动机相关的基因的表达，总体目标是为独立的职业生涯奠定科学和技术基础，以促进对基因-大脑-行为关系的理解，并开发预防和干预大脑疾病的方法，如成瘾、OBE攻击。

DESCRIPTION (provided by applicant): This application describes a systematic 5-years training plan to launch an independent research career neuroscience with emphasis on functional epigenetics and brain imaging. The overall goal of the Candidate contribute to the understanding of the biological mechanisms underlying brain function, specifically, to better I the role of individual variations in genetic and epigenetic makeup. To achieve this goal, a rigorous training plan, integrating didactic and research components tailored to candidate's goals, skills and experience is put together. Brookhaven National Laboratory (BNL) provides an IC environment to accomplish this training - it is a home to state-of-the-art functional neuroimaging technologies mentors of this project are distinguished scientists, preeminent experts in their areas. The research project of proposal implements the practical mean to achieve this goal. It aims to investigate the mechanisms by which (focus of the proposal is on monoamine oxidase A (MAOA) gene) affect brain function. The research will make use of the unique opportunity afforded by BNL: Positron Emission Tomograph enables direct measurement of the MAOA activity in the living human brain. PET data will be complemented t high-resolution epigenetic analysis. The overall goal of this research proposal is to investigate the contribution of epigenetic mechanism individual differences in brain chemistry with an overarching view to understand the neurobiological substrate underlying different behavioral phenotypes. We hypothesize that epigenetic mechanisms play an important role in the transcriptional regulation o MAOA gene which potentially contribute to variation in human behavior. To test this, we propose to interroga gene methylation and determine the variation in methylation across a group of normal individuals. Subsequer individual's methylation pattern will be linked to their brain imaging data measuring the amount of MAO A acti data will be(used to determine if there is a correlation between methylation of the MAOA gene and the amoun in the brain. The study will add new information by addressing a key unresolved question in brain science: What and biochemical-substrates underlie human behavior? Verified knowledge of the epigenetic regulation of this improve our general understanding of the interplay between genes and the environment, so adding a new ins brain biology. The project's main objective is to afford training needed for the candidate to initiate an independent career in neuroscience, particularly in neuroimaging and epigenetics. Pursuing this objective, the trainee will obtain valuable scientific data and significantly contribute to our understanding of the mechanisms regulating brain neurochemistry, thus add biochemical relevance to the growing number of reports of relationships between the MAOA genotype, environmental stressors and behavior. In this K01 application the candidate proposes a training program in brain imaging and genetics to stu affecting the expression of the genes involved in reward, arousal and motivation with the overarching goal to scientific and technical foundation for an independent career in advancing understanding of gene-brain-behavior relationships and the development of preventions and interventions for brain disorders such as addiction, obe aggression.