亨廷顿病中神经衰老向退行性疾病演变的机制研究

亨廷顿病是最主要的单基因遗传的神经退行性疾病之一，其疾病模型被广泛用于研究神经衰老向退行性疾病演变的机制。申请人在该重大研究计划培育项目的资助下，对亨廷顿病中神经退行的机制及相应干预策略进行了深入研究并取得了系列突破，发表通讯作者论文于Nature（入选其评选的年度十大杰出科技论文）、Nature Chemical Biology、Cell Research等期刊。在本项目中，申请人拟在前期研究的基础上，以亨廷顿病模型为主要的疾病模型，结合项目参与人余巍在衰老相关的去乙酰化酶Sirtuin家族研究领域的优势，从蛋白质稳态以及代谢（特别是线粒体功能）调控等不同角度研究神经衰老向退行演变的机制。本项目的成功实施将从多角度揭示亨廷顿病等神经退行性疾病发生发展的新机制，并开拓其根本性治疗的原创方法和潜在药物。

Huntington’s disease is one of the major monogenetic neurodegenerative disorders, and its models have been widely used for mechanistic studies of aging-associated neurodegeneration. With the funding support of one of the incubation projects from this “Major Research Plan” of NSFC, the applicant has made a series of breakthroughs in the mechanism of neurodegeneration and the potential therapeutic strategies of Huntington’s disease. The relevant research has been published in Nature, Nature Chemical Biology, Cell Research, etc., with the applicant as the corresponding author. One of the papers (Nature 2019) was selected as one of the “10 Remarkable Papers from 2019” by Nature. In this project, the applicant plans to use Huntington’s disease models as the major research material to perform mechanistic studies of aging-associated neurodegeneration from several different aspects including protein homeostasis and metabolism (especially mitochondria functions). The research plan has solid basis including the applicant’s previously published studies and preliminary results, as well as the expertise of Dr. Wei Yu, the participant of this project, on aging-related Sirtuin deacetylase family proteins' function in metabolism. Successful execution of this project will reveal novel mechanisms of neurodegeneration from different angles, identifying novel therapeutic strategies and potential drugs for the fundamental treatment of Huntington’s disease and similar neurodegenerative disorders.