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：
7341120
负责人：
MARC I DIAMOND
金额：
$ 34.49万
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/7341120
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

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 HD.

多聚谷氨酰胺神经退行性疾病是一个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识别多聚谷氨酰胺神经退行性疾病的分子机制，以确定具体的治疗目标，并开发基于机制的疗法。先前的工作表明 Y-27632， rho 相关激酶 p160ROCK 的抑制剂，可减少多聚谷氨酰胺聚集和细胞毒性和果蝇模型。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。我们还将分析来自生物活性化合物的两次先前筛选。将使用系统化的方式分析结果结合遗传和药理学方法来确定具有潜在意义的新途径。目标 2：确定 p160ROCK 信号传导影响聚谷氨酰胺的分子机制聚集和毒性。 p160ROCK信号通路特定成分的作用将被测试在果蝇中。将测试聚谷氨酰胺蛋白与肌动蛋白结合的分子基础，及其作用确定了调节多聚谷氨酰胺聚集的作用。目标 3：测试 Y-27632 的预防活性体内神经变性。 Y-27632在脑中的生物活性和全身毒性应按顺序测定计划适当的给药方案。 Y-27632 体内多聚谷氨酰胺依赖性病理的抑制应使用 R6/2 小鼠的各种行为、转棒、病理和生化分析进行测试高清模型。