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 重度抑郁症（MDD）是全球残疾的主要原因。 MDD的重要特征是昼夜节律 节奏疾病。最近的研究表明，使用A的基因表达（GE）节奏 验尸（PM）脑组织的“死亡时间”分析，其中GE数据在24小时的时钟上组织 基于个人死亡时间。使用这种方法，以前证明MDD受试者具有 包括纹状体在内的许多大脑区域中破坏了GE节奏。纹状体由 背侧纹状体和腹侧纹状体都暗示着压力，抗抗抑郁症和抑郁症。 初步研究，候选人表征了人类背侧的GE节奏和相位关系 和腹纹状体。驱动纹状体中GE的节奏模式的机制和改变 在MDD中观察到的仍有待研究。该K01提案利用多摩学方法来调查 DNA甲基化（DNAM）是抑郁症中GE节奏的潜在表观遗传机制。 鉴于（1）纹状体中的dnam在抑郁症中很大，直接受压力影响，（2） DNAM的节奏相关并与人类皮质中的GE节奏相关，中心假设是 抑郁症的纹状体GE节律破坏是由DNAM节奏的长期压力诱发的改变驱动的。 该假设将通过以下目的检验：（1）确定人类PM中DNAM的节奏变化 MDD受试者的背侧和腹侧纹状体； （2）采用多摩斯数据集成方法来确定 DNAM的节奏变化如何影响人类PM背和腹侧纹状体的整个转录组的节奏 在MDD主题中； （3）确定整个转录组的节奏和类似于Anhedonia的行为的调节 在慢性应激的小鼠模型中，通过DNAM在背侧和腹侧纹状体中。这些研究是 了解MDD中昼夜节律破坏的基础机制，并可能导致新颖的发现 将来治疗的治疗靶标。完成拟议的研究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破坏的表观遗传机制 在抑郁症中，候选人将需要培训：（1）发展概念和技术专长 在使用啮齿动物模型和人类PM脑组织来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； （3）学习高级生物统计学和 生物信息学技能以整合转录组学和表观基因组学数据的昼夜节律分析。实现这些 培训目标，候选人组建了一个心态团队，该团队在神经生物学方面具有广泛的专业知识 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，具有出色的职业发展机会，成为成功的环境 独立研究者。完成此提案后，候选人将被唯一地定位 自己的研究计划研究了抑郁症中昼夜节律中断的表观遗传机制。