Therapeutic Potential of Small Molecule Activators of the PINK1-Parkin Pathway

PINK1-Parkin 通路小分子激活剂的治疗潜力

基本信息

批准号：
8996662
负责人：
Leo J Pallanck
金额：
$ 7.73万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996662
关键词：
Alzheimer&apos s Disease Animal Model Biological Assay Cell Culture Techniques Chemical Agents Chemicals Childhood Collaborations Complex Cytochrome c Reductase Diabetes Mellitus Disease Disease model Drosophila genus Drosophila melanogaster Elderly Etiology Genes Goals Health Human In Vitro Inherited Laboratories Longevity Mitochondria Mitochondrial Diseases Modeling Mutation Nerve Degeneration Onset of illness PTEN gene Paralysed Parkin gene Parkinson Disease Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Quality Control Syndrome System Testing Therapeutic United States National Institutes of Health Vertebrates Work age related base curative treatments design efficacy testing feeding fly human disease mitochondrial DNA mutation mitochondrial dysfunction mutant neurodegenerative phenotype null mutation oligomycin sensitivity-conferring protein overexpression parkin gene/protein research study small molecule treatment strategy ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial DNA mutations cause a number of severe childhood-onset mitochondrial syndromes, and mitochondrial dysfunction is associated with common age-related diseases such as diabetes, Alzheimer's disease and Parkinson's disease. However, there are currently no curative treatments for any of these diseases. One promising avenue of therapy for mitochondrial diseases involves the use of chemical agents that can activate a cellular quality control pathway that is capable of selectively eliminating dysfunctional mitochondria. Recent work indicates that the PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin function in such a pathway. Moreover, our preliminary studies demonstrate that overexpression of PINK1 and Parkin in the fruit fly Drosophila melanogaster rescues fly models of mitochondrial disease, thus validating the therapeutic potential of this pathway. The goal of our proposal is to test whether PINK1-Parkin pathway activating compounds identified from high-throughput cell culture-based screens can also rescue fly models of mitochondrial disease. To achieve this goal, we propose two aims. First, we propose to test whether PINK1-Parkin pathway activating compounds identified from cell culture-based screens can rescue an easily assayed phenotype associated with our Drosophila models of mitochondrial disease. Second, we will test whether the most promising compounds identified in our first aim act in a PINK1 and Parkin-dependent fashion, and whether these compounds can rescue other phenotypes of our mitochondrial disease models. Our work will potentially identify compounds that can be used to treat a wide variety of human diseases.

描述（由申请人提供）：线粒体DNA突变导致许多严重的儿童期发病的线粒体综合征，线粒体功能障碍与常见的年龄相关疾病如糖尿病、阿尔茨海默病和帕金森病有关。然而，目前还没有针对这些疾病的治疗方法。线粒体疾病的一种有希望的治疗途径涉及使用化学试剂，该化学试剂可以激活细胞质量控制途径，从而能够选择性地消除功能失调的线粒体。最近的研究表明，PTEN 诱导的激酶 1 (PINK1) 和 E3 泛素连接酶 Parkin 在此类途径中发挥作用。此外，我们的初步研究表明，果蝇中PINK1和Parkin的过度表达可以挽救线粒体疾病的果蝇模型，从而验证了该途径的治疗潜力。我们提案的目标是测试从高通量细胞培养筛选中鉴定出的 PINK1-Parkin 通路激活化合物是否也能拯救线粒体疾病的果蝇模型。为了实现这一目标，我们提出两个目标。首先，我们建议测试从基于细胞培养的筛选中鉴定出的 PINK1-Parkin 通路激活化合物是否可以挽救与我们的果蝇线粒体疾病模型相关的易于分析的表型。其次，我们将测试我们第一个目标中确定的最有希望的化合物是否以 PINK1 和 Parkin 依赖性方式发挥作用，以及这些化合物是否可以挽救我们线粒体疾病模型的其他表型。我们的工作将有可能发现可用于治疗多种人类疾病的化合物。