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

• 批准号: 10563208
• 负责人: Carla Nasca
• 金额: $ 73.7万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10563208
• 关键词: Acceleration; Affect; Age; Anterior; Antibodies; Antidepressive Agents; Bioinformatics; Biological Assay; Brain; Carnitine O-Acetyltransferase; Cell Nucleus; Clinical; Clinical Course of Disease; Computational algorithm; Data; Development; Dimensions; Enzymes; Epigenetic Process; Exhibits; Foundations; Funding; Gene Expression; Genes; Glutamates; Goals; Histone Acetylation; Individual; Left; Levocarnitine Acetyl; Link; Maps; 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; Psychiatry; Randomized; Regulation; Remission Induction; 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; liquid chromatography mass spectrometry; magnetic beads; metabolomics; metabotropic glutamate receptor 2; mitochondrial metabolism; 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

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.

项目概要/摘要 难治性抑郁症 (TRD) 是全世界疾病和残疾的主要原因；缺乏新的机制模型来开发更好的治疗策略。迄今为止的研究表明，给予 LAC（一种关键的线粒体代谢物）可通过增加组蛋白乙酰转移酶 (HAT) 活性以及与 TRD 相关的回路中谷氨酸释放 mGlu2 受体的关键抑制剂的相关表达，从而导致快速且持久的抗抑郁样反应。此外，TRD 临床表型中 LAC 水平降低。本应用的目的是了解中枢和外周 LAC 相关线粒体代谢在 TRD 表型 TMS 反应调节中的作用。我们还将使用计算算法和统计聚类来确定 TMS 反应的新型生物标志物在功能连接轨迹中的作用，以及这些通路如何通过性别进行修改。这一贡献将增进我们对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。