Novel mechanisms of epigenetic regulation in stress and depression: toward a precision medicine model

压力和抑郁症表观遗传调控的新机制：走向精准医学模型

• 批准号: 10437038
• 负责人: Carla Nasca
• 金额: $ 40.98万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-23 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437038
• 关键词: Acetyl Coenzyme A; Affect; Antidepressive Agents; Behavior; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; Carnitine O-Acetyltransferase; Cell division; Cells; Chronic; Chronic stress; Clinical; Clinical Research; Cytosol; Data; Development; Disease; Enhancers; Enzymes; Epigenetic Process; Fatty Acids; Female; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomics; Glutamates; Goals; Hippocampus (Brain); Histocytochemistry; Histone Acetylation; Histone H3; Histones; Human; Incidence; Ketamine; Levocarnitine Acetyl; Lysine; Major Depressive Disorder; Maps; Mental Depression; Mental disorders; Mitochondria; Modeling; Molecular; Mus; Nature; Neuronal Plasticity; Neurons; Neurosciences Research; Nuclear; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Post-Translational Protein Processing; Proteins; Regulation; Reporting; Research; Resort; Risk Factors; Rodent; Role; Sex Differences; Signal Pathway; Social Interaction; Specificity; Stress; Synapses; Synaptic plasticity; Testing; Transcript; Woman; Work; biological adaptation to stress; dentate gyrus; disability; endophenotype; epigenetic regulation; epigenome; fatty acid oxidation; histone acetyltransferase; histone modification; inhibitor; male; men; metabotropic glutamate receptor 2; mitochondrial metabolism; neurobiological mechanism; novel; personalized strategies; pre-clinical; precision medicine; receptor; resilience; response; restraint stress; sex; sexual dimorphism; small hairpin RNA; stem; stress related disorder; therapeutic target; tool; trafficking; transcriptome sequencing; transcriptomics; treatment strategy; treatment-resistant depression

PROJECT SUMMARY/ABSTRACT Depression is a leading cause of illness and disability worldwide, with a two-fold higher incidence in women than men. Stress is a well-established risk factor for depression. Studies to date showed that stress leads to epigenetic reprogramming of gene expression key for neuronal plasticity of brain circuits such as the ventral hippocampus, which has been implicated in depression. We previously reported that: 1) administration of acetyl-L-carnitine (LAC), leads to a rapid and persistent antidepressant-like response by increasing a chronic stress-induced suppression of H3K27ac and the related expression of a key inhibitor of glutamate release mGlu2 receptor in vDG glutamatergic neurons; and 2) LAC levels are decreased in subjects suffering from depression. The objective of this application is to understand the role of LAC-related mitochondrial metabolism in the regulation of stress responses. This contribution will advance our understanding of cellular and molecular mechanisms of mitochondrial metabolism for stress responses, and identify sex-differences in these mechanisms.

项目摘要/摘要 抑郁症是世界范围内疾病和残疾的主要原因，女性的发病率是男性的两倍。压力是抑郁症的一个公认的风险因素。到目前为止的研究表明，压力会导致大脑回路神经元可塑性的关键基因表达的表观遗传重新编程，例如腹侧海马体，这与抑郁症有关。我们先前报道：1)给予乙酰肉碱(LAC)，通过增加慢性应激诱导的H3K27ac抑制和VDG谷氨酸能神经元中谷氨酸释放的关键抑制因子mGlu2受体的相关表达，导致快速而持久的抗抑郁剂样反应；以及2)抑郁症患者的LAC水平降低。这项应用的目的是了解LAC相关线粒体代谢在应激反应调节中的作用。这一贡献将促进我们对应激反应中线粒体代谢的细胞和分子机制的理解，并识别这些机制中的性别差异。