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

项目总结/摘要 难治性抑郁症（TRD）是世界范围内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）活性和与TRD相关的回路中谷氨酸释放mGlu 2受体关键抑制剂的相关表达，导致快速和持续的抗抑郁样反应。此外，LAC水平在TRD的临床表型中降低。本申请的目的是了解TRD表型中中枢和外周LAC相关线粒体代谢在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反应的新生物标志物在功能连接轨迹中的作用，以及这些途径如何通过性别进行修改。这一贡献将促进我们对TRD表型中TMS反应的线粒体代谢的细胞和分子机制的理解，并确定这些机制的性别差异。

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.