NAD, PGC-1alpha and SIRT3 as Therapeutics Targets for Huntington's Disease

NAD、PGC-1α 和 SIRT3 作为亨廷顿病的治疗靶点

基本信息

批准号：
9197703
负责人：
M FLINT BEAL
金额：
$ 37.08万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197703
关键词：
Agonist Atrophic Autopsy Bexarotene Biogenesis Body Weight decreased Brain Brown Fat CAG repeat Clinic Clinical Clinical Trials Cognitive Corpus striatum structure Deacetylase Development Diet Disease Fenofibrate Gene Expression Genetic Genetic Transcription Goals Huntington Disease Huntington gene Impairment In Vitro Intervention Mitochondria Motor Mus Muscle NIH Program Announcements Nerve Degeneration Neurodegenerative Disorders Neurons Pathogenesis Pathology Performance Peroxisome Proliferator-Activated Receptors Pharmacology Proteins RXR SIRT1 gene Stretching Therapeutic Therapeutic Agents Toxic effect Transcription Coactivator Transgenic Mice Up-Regulation Validation antioxidant enzyme brain tissue disability improved mitochondrial dysfunction motor deficit mouse model mutant neuropathology neuroprotection nicotinamide-beta-riboside overexpression oxidative damage polyglutamine preclinical development public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease leading to both cognitive as well as motor deficits, and severe disability. The disease is caused by an unstable CAG repeat expansion which leads to a polyglutamine stretch within the protein huntingtin. The toxic effects of mutant huntingtin result in transcriptional dysregulation as well as mitochondrial dysfunction and oxidative damage. There is a deficiency of PGC-1alpha, a transcriptional coactivator which controls mitochondrial biogenesis and expression of antioxidant enzymes. There is also a deficiency of SIRT3, which is a protein deacetylase whose expression within mitochondria is dependent on PGC-1alpha. We propose validating both PGC-1alpha and SIRT3 as therapeutic targets for the treatment of HD. We will determine whether crossing both R6/2 and KI-zQ175 mice with SIRT3 overexpressing mice will produce neuroprotective effects. We will administer nicotinamide riboside (NR) in the diet as a means of activating SIRT1 and SIRT3, and determine whether this produces neuroprotective effects in both the R6/2 and the BACHD transgenic mouse models of HD. Lastly we will determine whether administration of the panPPAR agonist fenofibrate, or the RXR agonist bexarotene either alone or in combination will increase PGC-1alpha expression and exert neuroprotective effects in R6/2 and BACHD transgenic mice. These studies will validate PGC-1alpha and SIRT3 as therapeutic targets, and will determine whether NR, fenofibrate and bexarotene are suitable for further preclinical development, and ultimately for clinical trials to establish efficacy as neuroprotective therapies for HD.

描述（由申请人提供）：亨廷顿病（HD）是一种常染色体显性遗传性进行性神经退行性疾病，会导致认知和运动缺陷以及严重残疾。该疾病是由不稳定的 CAG 重复扩张引起的，导致内部多聚谷氨酰胺伸展。亨廷顿蛋白突变体的毒性作用会导致转录失调以及线粒体功能障碍和氧化损伤。PGC-1α是一种控制转录的辅激活因子。 SIRT3 是一种蛋白质脱乙酰酶，其在线粒体内的表达依赖于 PGC-1α，我们建议验证 PGC-1α 和 SIRT3 作为 HD 的治疗靶点。我们将确定 R6/2 和 KI-zQ175 小鼠与 SIRT3 过表达小鼠杂交是否会产生神经保护作用。我们将施用烟酰胺核苷。 (NR) 作为激活 SIRT1 和 SIRT3 的一种手段，并确定这是否在 HD 的 R6/2 和 BACHD 转基因小鼠模型中产生神经保护作用。 RXR 激动剂贝沙罗汀单独或联合使用会增加 R6/2 和 BACHD 转基因小鼠中 PGC-1α 的表达并发挥神经保护作用。研究将验证 PGC-1α 和 SIRT3 作为治疗靶点，并将确定 NR、非诺贝特和贝沙罗汀是否适合进一步的临床前开发，并最终进行临床试验以确定 HD 神经保护疗法的功效。