Role of DNA methylation in regulating striatal molecular rhythm alterations in depression

DNA甲基化在调节抑郁症纹状体分子节律改变中的作用

• 批准号: 10348253
• 负责人: Kyle Ketchesin
• 金额: $ 17.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348253
• 关键词: Affect; Anhedonia; Antidepressive Agents; Automobile Driving; Autopsy; Behavior; Behavioral; Bioinformatics; Biometry; Body Temperature; Brain; Brain region; Cessation of life; Chronic; Chronic stress; Circadian Dysregulation; Circadian Rhythms; Cognition; Corpus striatum structure; DNA Methylation; DNA Modification Methylases; DNA methylation profiling; DNA methyltransferase inhibition; Data; Decision Making; Dorsal; Environment; Environmental Risk Factor; Epigenetic Process; Feedback; Funding; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Hormones; Hour; Human; Individual; Laboratories; Lead; Learning; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Mentors; Mentorship; Midbrain structure; Modification; Molecular; Motivation; Multiomic Data; Mus; Neurobiology; Nucleus Accumbens; Periodicity; Phase; Positioning Attribute; Psychiatry; Regulation; Research; Research Personnel; Rest; Rodent; Rodent Model; Role; Sleep; Sleep Wake Cycle; Stress; Technical Expertise; Testing; Time; Tissues; Training; Transcript; Universities; Ventral Striatum; Viral; base; brain tissue; career; career development; circadian; circadian pacemaker; data integration; depressive symptoms; disability; epigenome; epigenomics; imaging study; mouse model; multiple omics; new therapeutic target; programs; putamen; skills; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a leading global cause of disability. A prominent feature of MDD is circadian rhythm disturbances. Recent studies have shown gene expression (GE) rhythms in the human brain using a “time of death” analysis of postmortem (PM) brain tissue, where GE data is organized across a 24-hour clock based on individual time of death. Using this approach, it was previously shown that MDD subjects have disrupted GE rhythms across a number of brain regions, including the striatum. The striatum is composed of the dorsal striatum and ventral striatum and both have been implicated in stress, anhedonia, and depression. In preliminary studies, the candidate characterized GE rhythms and phase relationships across the human dorsal and ventral striatum. The mechanisms driving these rhythmic patterns of GE in the striatum and the alterations observed in MDD remain to be investigated. This K01 proposal utilizes a multi-omics approach to investigate DNA methylation (DNAm) as a potential epigenetic mechanism by which GE rhythms are altered in depression. Given that (1) DNAm in the striatum is strongly implicated in depression and directly influenced by stress and (2) DNAm rhythms are correlated and time-locked to GE rhythms in the human cortex, the central hypothesis is that striatal GE rhythm disruptions in depression are driven by chronic-stress induced alterations in DNAm rhythms. This hypothesis will be tested by the following aims: (1) Determine rhythmic changes in DNAm in the human PM dorsal and ventral striatum in MDD subjects; (2) Employ a multi-omics data integration approach to determine how rhythmic changes in DNAm affect transcriptome-wide rhythms in the human PM dorsal and ventral striatum in MDD subjects; and (3) Determine the regulation of transcriptome-wide rhythms and anhedonia-like behavior by DNAm in the dorsal and ventral striatum in a mouse model of chronic stress. These studies are central to understanding the mechanisms underlying circadian disruptions in MDD and may result in the discovery of novel therapeutic targets for future treatments. To complete the proposed studies and support his career goal of establishing an independent laboratory to study the epigenetic mechanisms driving circadian rhythm disruptions in depression, the candidate will require mentored training in: (1) developing conceptual and technical expertise in the use of rodent models and human PM brain tissue to study the neurobiology of depression; (2) developing conceptual and technical expertise in the field of epigenetics; and (3) learning advanced biostatistics and bioinformatics skills to integrate circadian analyses of transcriptomics and epigenomics data. To achieve these training goals, the candidate has assembled a mentorship team with extensive expertise in the neurobiology of depression, epigenetics, and biostatistics. The Department of Psychiatry at the University of Pittsburgh offers a well-funded environment with exceptional career development opportunities to become a successful independent investigator. At completion of this proposal, the candidate will be uniquely positioned to lead his own research program studying the epigenetic mechanisms driving circadian rhythm disruptions in depression.

项目摘要/摘要 严重抑郁障碍(MDD)是导致残疾的全球主要原因。MDD的一个显著特征是昼夜节律。 节律紊乱。最近的研究表明，人类大脑中的基因表达(GE)节律使用 对死后(PM)脑组织的“死亡时间”分析，其中GE数据是跨24小时时钟组织的 根据个人死亡时间。使用这种方法，以前已经表明MDD受试者有 扰乱了大脑多个区域的GE节律，包括纹状体。纹状体由以下部分组成： 背侧纹状体和腹侧纹状体以及两者都与应激、快感缺乏和抑郁有关。在……里面 初步研究表明，这位候选人描述了人体背部的GE节律和位相关系 和腹侧纹状体。纹状体Ge节律性变化的机制及其变化 在MDD中观察到的情况仍有待调查。K01提案使用多组学方法来研究 DNA甲基化(DNaM)作为一种潜在的表观遗传机制，在抑郁症中改变GE节律。 鉴于(1)纹状体中的dNaM与抑郁症密切相关，并直接受到压力的影响，以及(2) 在人类皮质中，dNaM节律与GE节律相关并时序锁定，中心假设是 抑郁症患者纹状体GE节律紊乱是由慢性应激引起的dNaM节律改变所致。 这一假说将通过以下目的来检验：(1)确定人类PM中dNaM的节律性变化 MDD受试者的背侧和腹侧纹状体；(2)使用多组学数据集成方法确定 DNaM的节律性变化如何影响人PM背侧和腹侧纹状体的转录组节律 在MDD受试者中；以及(3)确定转录组范围的节律和快感缺乏样行为的调节 通过dNaM在慢性应激小鼠模型的背侧和腹侧纹状体。这些研究是 了解MDD昼夜节律紊乱的潜在机制并可能导致新的发现 未来治疗的治疗目标。完成拟议的学习并支持他的职业目标 建立一个独立的实验室来研究驱动昼夜节律紊乱的表观遗传机制 在抑郁症中，应聘者需要接受以下方面的指导培训：(1)发展概念和技术专长 利用啮齿动物模型和人类PM脑组织研究抑郁症的神经生物学；(2)发展 表观遗传学领域的概念和技术专长；以及(3)学习高级生物统计学和 整合转录组和表观基因组数据的昼夜节律分析的生物信息学技能。要实现这些目标 根据培训目标，应聘者组建了一支在神经生物学方面具有广泛专业知识的指导团队 抑郁症、表观遗传学和生物统计学。匹兹堡大学精神病学系提供 资金充足的环境，拥有卓越的职业发展机会，成为一名成功的 独立调查员。在这项提议完成后，候选人将处于独特的地位，领导他的 自己的研究项目，研究抑郁症昼夜节律紊乱的表观遗传机制。