A genome-wide approach to the epigenetics of stress and depression

压力和抑郁症表观遗传学的全基因组方法

• 批准号: 8337386
• 负责人: James B. Potash
• 金额: $ 34.81万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337386
• 关键词: Adverse effects; Amygdaloid structure; Anhedonia; Antidepressive Agents; Anxiety; Behavior; Behavioral; Biological Markers; Blood; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Nucleus; Chronic; Corticosterone; Corticotropin; DNA; DNA Methylation; Data; Development; Disease; Disease remission; Effectiveness; Endocrine; Epigenetic Process; Etiology; Fluoxetine; Functional disorder; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Glean; Health; Hippocampus (Brain); Histones; Human; Hybridization Array; Hypothalamic structure; Imipramine; Lead; Location; Lymphocyte; Major Depressive Disorder; Medial; Mediating; Mental Depression; Mental disorders; Methods; Methylation; Modeling; Modification; Molecular; Mus; Neurobiology; Neuronal Plasticity; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Prefrontal Cortex; Public Health; Regulation; Relative (related person); Research Personnel; Rodent; Rodent Model; Role; Social Interaction; Stress; Testing; Testosterone; Validation; Work; base; biological adaptation to stress; bisulfite; demethylation; dentate gyrus; depressive symptoms; disability; epigenomics; genome-wide; histone modification; improved; insight; mouse model; neurogenesis; novel; paraventricular nucleus; public health relevance; research study; response; social; social stress; success; tool; treatment response

DESCRIPTION (provided by applicant): We propose to determine the epigenetic contribution to depression, the most common debilitating psychiatric disorder, through a highly focused approach that combines cutting-edge epigenomic analysis with a stress-based mouse model of the illness. Stress is known to play a major role in triggering major depressive disorder (MDD), likely through interaction with genetic vulnerability factors. Recent work showing stress-mediated epigenetic control of BDNF, a gene that plays a key role in depression and antidepressant response, provides molecular evidence that epigenetic mechanisms can mediate this interaction. Additional recent work from a Co- Investigator at Johns Hopkins shows that DNA demethylation of genes including Bdnf plays a role in neural plasticity and neurogenesis in response to electroconvulsive stimulation. These results suggest the possibility that new insights into the etiology and pathophysiology of depression, and into the mechanisms of treatment response, can be gleaned from a genome- wide epigenetic approach to the study of stress-induced, and medication reversed, changes in rodent brain DNA. The tools to perform genome-wide epigenetic studies have only just become available and our Epigenetics Center at Johns Hopkins has been a leader in the development of such tools, having created the Comprehensive Hybridization Arrays for Relative Methylation (CHARM) method for genome-wide DNA methylation (DNAm) studies. In addition to our epigenomics expertise, our team also has expertise in the other facets of this project that are crucial to its success, including rodent models of stress, the genetics of depression, and neurobiology. We intend to test the following specific aims: 1) determine the behavioral and endocrine outcomes of chronic social stress and their persistence or reversibility by antidepressant drug treatment; 2) test whether social stress results in depressive-like behaviors through epigenetic modifications; and 3) validate and extend top DNAm difference findings through study of gene expression, DNAm in other brain regions, DNAm in blood, and histone modifications in genes. PUBLIC HEALTH RELEVANCE: We propose to determine the epigenetic contribution to major depressive disorder (MDD), the most common debilitating psychiatric disorder, through a highly focused approach that combines cutting-edge epigenomic analysis with a mouse model of stress-induced depression. MDD is among the world's most important public health problems, as it is the fourth leading cause of disability globally and projected to rise to second by 2020. By identifying genomic locations where stress changes DNA methylation in the brain, we hope to glean fundamental new insights into the pathogenesis of depression and thus advance the effort to improve treatments for this illness.

描述（由申请人提供）：我们建议通过高度集中的方法，将前沿的表观基因组分析与基于压力的疾病小鼠模型相结合，确定表观遗传对抑郁症（最常见的衰弱性精神疾病）的影响。众所周知，压力可能是通过与遗传脆弱性因素相互作用而在引发重度抑郁症 (MDD) 方面发挥重要作用。最近的研究表明，应激介导的 BDNF 表观遗传控制（BDNF 是一种在抑郁症和抗抑郁反应中发挥关键作用的基因）提供了分子证据，表明表观遗传机制可以介导这种相互作用。约翰·霍普金斯大学的一位联合研究员最近的其他工作表明，包括 Bdnf 在内的基因 DNA 去甲基化在响应电休克刺激的神经可塑性和神经发生中发挥着作用。这些结果表明，通过全基因组表观遗传学方法来研究压力引起的和药物逆转的啮齿动物大脑变化，可以对抑郁症的病因学和病理生理学以及治疗反应机制产生新的见解。脱氧核糖核酸。进行全基因组表观遗传学研究的工具刚刚面世，我们约翰·霍普金斯大学的表观遗传学中心一直是此类工具开发的领导者，创建了用于全基因组 DNA 的相对甲基化综合杂交阵列 (CHARM) 方法甲基化（DNAm）研究。除了我们的表观基因组学专业知识之外，我们的团队还拥有对该项目的成功至关重要的其他方面的专业知识，包括啮齿动物压力模型、抑郁症遗传学和神经生物学。我们打算测试以下具体目标：1）确定慢性社会压力的行为和内分泌结果及其通过抗抑郁药物治疗的持续性或可逆性； 2）测试社会压力是否通过表观遗传修饰导致抑郁样行为； 3) 通过研究基因表达、其他大脑区域的 DNAm、血液中的 DNAm 和基因中的组蛋白修饰来验证和扩展最重要的 DNAm 差异发现。 公共健康相关性：我们建议通过高度集中的方法，将前沿的表观基因组分析与压力诱发抑郁症的小鼠模型相结合，确定表观遗传对重度抑郁症（MDD）（最常见的使人衰弱的精神疾病）的影响。 MDD 是世界上最重要的公共卫生问题之一，因为它是全球第四大残疾原因，预计到 2020 年将升至第二位。通过确定压力改变大脑 DNA 甲基化的基因组位置，我们希望获得基本的新见解深入研究抑郁症的发病机制，从而推动改善这种疾病的治疗方法。