Regulation of Polyglutamine Aggregation and Toxicity

聚谷氨酰胺聚集和毒性的调节

基本信息

批准号：
7168427
负责人：
MARC I DIAMOND
金额：
$ 34.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-15 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7168427
关键词：
Actins Affinity Androgens Attention Behavior Binding Biochemical Biochemistry Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cells Classification Complement Cytoskeleton Data Diamond Disease Dose Drosophila genus Drug Delivery Systems Family Fluorescence Resonance Energy Transfer Genetic Goals Huntington Disease Inborn Genetic Diseases Laboratories Libraries Mammals Mediating Modeling Modification Molecular Molecular Target Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathologic Pathology Pathway interactions Phosphorylation Phosphotransferases Protein Conformation Proteins Regulation Regulatory Pathway Research Personnel Rho-associated kinase Role Screening procedure Signal Pathway Signal Transduction Spinobulbar Muscular Atrophy System Testing Toxic effect Treatment Protocols Work base cell growth regulation chemical genetics cofilin high throughput screening human Huntingtin protein in vivo inhibitor/antagonist mouse model novel polyglutamine prevent programs protein misfolding small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Polyglutamine neurodegenerative diseases are a devastating family of inherited disorders that include Huntington Disease and spinobulbar muscular atrophy (SBMA). Long-term goals of this project are to identify molecular mechanisms of polyglutamine neurodegenerative disease, to determine specific therapeutic targets, and to develop mechanism-based therapies. Previous work demonstrated that Y-27632, an inhibitor of the rho-associated kinase p160ROCK, reduced polyglutamine aggregation and toxicity in cell and Drosophila models. Aim 1: Identify and characterize novel regulatory pathways and target molecules. We will complete a screen of a library of biologically active small molecules. We will also analyze hits from two prior screens of biologically active compounds. Results will be analyzed in a systematic fashion using a combination of genetic and pharmacologic approaches to determine new pathways of potential significance. Aim 2: Determine the molecular mechanism by which p160ROCK signaling influences polyglutamine aggregation and toxicity. The role of specific components of the p160ROCK signaling pathway will be tested in Drosophila. The molecular basis of polyglutamine protein association with actin will be tested, and its role in modulating polyglutamine aggregation determined. Aim 3: Test the activity of Y-27632 in preventing neurodegeneration in vivo. Bioactivity of Y-27632 in brain, and systemic toxicity shall be determined in order to plan an appropriate dosing regimen. Y-27632 inhibition of polyglutamine-dependent pathology in vivo shall be tested using a variety of behavior, rotarod, pathological and biochemical analyses in the R6/2 mouse model of Huntington's disease.

描述（由申请人提供）：多聚谷氨酰胺神经退行性疾病是一种破坏性的遗传性疾病家族，包括亨廷顿病和脊髓延髓肌萎缩症（SBMA）。该项目的长期目标是确定多聚谷氨酰胺神经退行性疾病的分子机制，确定特定的治疗靶点，并开发基于机制的疗法。先前的研究表明，Rho 相关激酶 p160ROCK 的抑制剂 Y-27632 可减少细胞和果蝇模型中的多聚谷氨酰胺聚集和毒性。目标 1：识别并表征新的调控途径和靶分子。我们将完成生物活性小分子库的筛选。我们还将分析之前两次筛选的生物活性化合物的命中结果。将结合遗传和药理学方法以系统的方式分析结果，以确定具有潜在意义的新途径。目标 2：确定 p160ROCK 信号传导影响多聚谷氨酰胺聚集和毒性的分子机制。 p160ROCK 信号通路特定成分的作用将在果蝇中进行测试。将测试聚谷氨酰胺蛋白与肌动蛋白结合的分子基础，并确定其在调节聚谷氨酰胺聚集中的作用。目标3：测试Y-27632在体内预防神经变性的活性。应确定 Y-27632 在脑中的生物活性和全身毒性，以便规划适当的给药方案。 Y-27632 对多聚谷氨酰胺依赖性病理的体内抑制应在亨廷顿病的 R6/2 小鼠模型中使用各种行为、旋转、病理和生化分析进行测试。