A translational approach for novel mechanisms of epigenetic regulation in treatment responses: toward a precision medicine model

治疗反应中表观遗传调控新机制的转化方法：走向精准医学模型

基本信息

批准号：
10344520
负责人：
Carla Nasca
金额：
$ 75.36万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-08 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10344520
关键词：
Affect Age Anterior Antibodies Antidepressive Agents Bioinformatics Biological Assay Brain Carnitine O-Acetyltransferase Cell Nucleus Clinical Clinical Course of Disease Computational algorithm Data Development Disease remission Enzymes Epigenetic Process Exhibits Foundations Funding Gene Expression Genes Glutamates Goals Histone Acetylation Individual Left Levocarnitine Acetyl Link Liquid substance Maps Mass Spectrum Analysis Metabolic Methodology Mitochondria Modeling Molecular Molecular Target Monitor Nature Neuronal Plasticity Neurons Pathway interactions Patients Peripheral Phenotype Plasma Polymers Positioning Attribute Precipitation Prefrontal Cortex Prevalence Protocols documentation Randomized Regulation Research Rest Rodent Model Role Severities Sex Differences Signal Pathway Specificity Testing Therapeutic Time United States National Institutes of Health Work clinical phenotype cost depression model depressive symptoms disability epigenetic regulation exosome fatty acid oxidation hippocampal pyramidal neuron histone acetyltransferase in vivo inhibitor innovation insight interest magnetic beads metabolomics metabotropic glutamate receptor 2 mitochondrial metabolism model development molecular phenotype multidisciplinary novel novel marker novel strategies novel therapeutic intervention personalized medicine pre-clinical precision medicine preclinical study predictive marker predictive modeling receptor response sex sexual dimorphism stem therapeutic target translational approach treatment response treatment-resistant depression

项目摘要

PROJECT SUMMARY/ABSTRACT Treatment resistant depression (TRD) is a leading cause of illness and disability worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Studies to date showed that administration of LAC, a pivotal mitochondrial metabolite, leads to a rapid and persistent antidepressant-like response by increasing histone acetyltransferases (HATs) activity and the related expression of a key inhibitor of glutamate release mGlu2 receptor in circuits implicated in TRD. Furthermore, LAC levels are decreased in clinical phenotypes of TRD. The objective of this application is to understand the role of central and peripheral LAC-related mitochondrial metabolism in the regulation of TMS responses in phenotypes of TRD. We will also use computational algorithm and statistical clustering to ascertain the role of the novel biomarkers of TMS responses in the trajectories of functional connectivity, and how these pathways are modified by sex. This contribution will advance our understanding of cellular and molecular mechanisms of mitochondrial metabolism for TMS responses in phenotypes of TRD, and identify sex-differences in these mechanisms.

项目摘要/摘要耐药抑郁症（TRD）是全球疾病和残疾的主要原因。缺乏用于发展更好治疗策略的新机械模型。迄今为止的研究表明，通过增加组蛋白乙酰基转移酶（HATS）活性，LAC（一种关键的线粒体代谢产物）的给药会导致快速且持续的抗抑郁样反应，以及与TRD中有关Circuits中谷氨酸释放MGLU2受体的关键抑制剂的关键抑制剂的相关表达。此外，TRD的临床表型中的LAC水平降低。该应用的目的是了解与TRD表型中TMS响应调节中心和外围LAC相关的中枢和外围LAC相关的代谢的作用。我们还将使用计算算法和统计聚类来确定TMS响应的新型生物标志物在功能连通性轨迹中的作用，以及如何通过性别修改这些途径。这种贡献将提高我们对TRD表型中TMS反应的线粒体代谢的细胞和分子机制的理解，并确定这些机制中的性别差异。