Epigenetic Mechanisms of Depression

描述（由申请人提供）：这个新的Conte中心的目标是最大限度地利用染色质生物学的最新进展，即所谓的表观遗传学，从根本上增加我们对导致抑郁症和介导抗抑郁反应的大脑长期异常的理解。我们的工作将集中在关键的边缘脑区域，核丘脑（NAc）和前额叶皮层（PFC）的几个区域，这些区域直接涉及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，埃里克·内斯特勒（西奈山）， Schahram Akbarian（马萨诸塞大学），大卫阿利斯（洛克菲勒）和卡罗尔Tamminga（UT西南），是谁拥有有效合作的历史，并将利用他们的互补专业知识和方法来制定拟议的研究多学科课程在各自领域的领导者。项目1，2和3，分别由Nestler，Akbarian和Allis博士领导，将描述在动物生命周期中一系列抑郁症动物模型中大脑边缘系统区域内表观遗传机制的作用。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。该中心由三个核心支持，一个是行政核心，负责监督和协调中心的运作;一个是染色质和基因分析核心，提供先进的最先进的方法和生物信息学，以表征抑郁症和抗抑郁作用中边缘区域染色质修饰的全基因组调控;和一个动物模型核心，提供最复杂的抑郁症动物模型，沿着先进的工具，（病毒介导的基因转移和小鼠中的诱导突变）来操纵边缘系统结构内感兴趣的个体基因，从而为抑郁症相关现象中表观遗传调控的参与提供因果证据。我们对这项关于抑郁症表观遗传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压力相关疾病进行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.