Epigenetic Mechanisms of Depression

描述(申请人提供)：这个新的孔特中心的目标是最大限度地利用染色质生物学，即所谓的表观遗传学的最新进展，从根本上增加我们对大脑中导致抑郁和调节抗抑郁反应的长期异常的理解。我们的工作将集中在关键的边缘脑区，伏隔核(NAC)和前额叶皮质(PFC)的几个区域，这些区域已经直接涉及到健康和疾病中的情绪控制。该中心由四所不同大学的四个项目组成。四个PI，Eric Nestler(西奈山)， 沙赫拉姆·阿克巴里安(马萨诸塞州大学)、大卫·阿利斯(洛克菲勒大学)和卡罗尔·塔明加(德克萨斯大学西南分校)是各自领域的领导者，他们已经建立了有效合作的历史，并将利用他们互补的专业知识和方法在拟议的研究中规划一条多学科的路线。项目1、项目2和项目3将分别由Nestler博士、Akbarian博士和Allis博士领导，将描述在动物生命周期的一系列抑郁症动物模型中，大脑边缘区域的表观遗传机制所扮演的角色。由Tamminga博士领导的项目4将把这些在动物身上的发现转化为人类死后的脑组织，从而为人类抑郁症的基础研究提供必要的验证。该中心得到三个核心的支持，一个是行政核心，负责监督和协调中心的运作；一个染色质和基因分析核心，提供先进的方法和生物信息学，以确定抑郁症边缘区域染色质修饰的基因组调控和抗抑郁作用；以及动物模型核心，用于提供最复杂的抑郁症动物模型，以及先进的工具(病毒介导的基因转移和小鼠的诱导突变)，以操纵边缘结构内的单个感兴趣基因，从而为表观遗传调控参与抑郁症相关现象提供因果证据。我们对这项关于抑郁症的表观遗传学基础的新颖而开创性的研究感到非常兴奋，我们相信这将有助于推动该领域对抑郁症和其他与压力相关的疾病进行显著更好的治疗和诊断测试。

DESCRIPTION (provided by applicant): The objective of this new Conte Center is to take maximal advantage of recent advances in chromatin biology, so-called epigenetics, to fundamentally increase our understanding of the long-lasting abnormalities in the brain that cause depression and that mediate antidepressant responses. Our work will focus on key limbic brain regions, nucleus accumbens (NAc) and several areas of prefrontal cortex (PFC), which have been implicated directly in the control of mood in health and disease. The Center is composed of four Projects at four different universities. The four PIs, Eric Nestler (Mount Sinai), Schahram Akbarian (UMass), David Allis (Rockefeller), and Carol Tamminga (UT Southwestern), are leaders in their fields who have an established history of effective collaboration and will use their complementary expertise and approaches to chart a multidisciplinary course in the proposed research. Projects 1, 2, and 3, lead by Drs. Nestler, Akbarian, and Allis, respectively, will characterize the role of epigenetic mechanisms within the brain's limbic regions in a range of animal models of depression over the life cycle of the animals. Project 4, lead by Dr. Tamminga, will translate these findings in animals to human postmortem brain tissue and thereby provide essential validation of the basic research for human depression. The Center is supported by three Cores, an Administrative Core to oversee and coordinate the Center's operations; a Chromatin and Gene Analysis Core to provide advanced state-of-the-art methods and bioinformatics to characterize genome-wide regulation of chromatin modifications in limbic regions in depression and antidepressant action; and an Animal Models Core to provide the most sophisticated animal models of depression along with the advanced tools (viral-mediated gene transfer and inducible mutations in mice) to manipulate individual genes of interest within limbic structures and thereby provide causal evidence for the involvement of epigenetic regulation in depression-related phenomena. We are very excited about this novel and pioneering investigation of the epigenetic underpinnings of depression, which we believe will help drive the field toward dramatically better treatments and diagnostic tests for depression and other stress-related illnesses.