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

基本信息

批准号：
10401550
负责人：
Carla Nasca
金额：
$ 42.38万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-23 至 2021-11-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401550
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/antagonist 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

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/antagonist 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

展开

项目摘要

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/摘要抑郁症是全球疾病和残疾的主要原因，女性的发病率比男性高两倍。压力是抑郁症的公认风险因素。迄今为止的研究表明，应力导致基因表达关键的表观遗传重编程，用于脑电路的神经元可塑性，例如腹侧海马，这与抑郁症有关。我们先前报道说：1）通过增加慢性应激诱导的H3K27AC抑制和谷氨酸释放MGLU2受体INVDG GlutamamatamatamAtamAdamatamatamAdamatamAdaramatametaMataramAtaramatametaMationGiic神经元的关键抑制剂，通过增加慢性应激诱导的H3K27AC抑制和相关表达，从而导致快速且持续的抗抑郁药样反应。 2）患有抑郁症的受试者的LAC水平降低。该应用的目的是了解与LAC相关的线粒体代谢在压力反应调节中的作用。这项贡献将提高我们对线粒体代谢的细胞和分子机制的理解，以应对压力反应，并确定这些机制中的性别差异。