Hsp40 and conformational disease

Hsp40 与构象疾病

• 批准号: 7548135
• 负责人: DOUGLAS M CYR
• 金额: $ 32.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548135
• 关键词: Address; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Binding; Biogenesis; Biological Assay; C-terminal; Cell Death; Cell Nucleus; Cell Wall; Cell membrane; Cells; Cellular biology; Cytoprotection; Cytosol; Data; Defense Mechanisms; Dementia; Detergents; Disease; Glutamine; Huntington Disease; Huntington protein; Molecular Chaperones; Molecular Conformation; Monitor; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathway interactions; Play; Prions; Proteins; Quality Control; Research; Role; Seminal; Specific qualifier value; Structure; System; Testing; Thioflavin T; Toxic effect; Yeasts; amyloid fibril formation; amyloid formation; base; conformer; cytotoxic; design; killings; monomer; non-prion; novel; overexpression; polyglutamine; prevent; prion biogenesis; protein aggregate; protein aggregation; protein folding; protein misfolding; therapeutic target; trafficking; yeast prion

DESCRIPTION (provided by applicant): Conformational diseases are neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause dementia and cell death via unknown mechanisms. Hsp40s are molecular chaperones that direct Hsp70 to interact with disease related proteins and partition them between pathways for folding, aggregation and amyloid formation. Prions are infectious proteins that that assemble into a self-perpetuating amyloid-like state that is associated with neurodegeneration. The study of yeast prions has provided many of the basic details about chaperone function in amyloid fibril formation. In preliminary studies we developed a number of assays to monitor Hsp40 action in modulating amyloid formation and toxicity. The studies proposed herein are designed to define mechanisms by which aberrant prion biogenesis causes cell death. In addition, we seek to identify the specific steps in prion assembly that are catalyzed by different Hsp40s. Finally, we will determine the structure and functional features of Type I and II Hsp40 sub-types that specify their action in prion biogenesis. The data obtained from these studies will define the rules for Hsp40 function in amyloid formation and identify therapeutic targets for the treatment of conformational disease. Conformational diseases are a neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause deimentia and cell death via unknown mechanisms. The data obtained from the proposed studies will define the rules for Hsp40 function in modulation of amyloid formation and toxicity and identify therapeutic targets for the treatment of conformational disease.

描述(申请人提供)：构象疾病是一种神经退行性疾病，在这种疾病中，淀粉样纤维状异常折叠蛋白的积累通过未知的机制导致痴呆和细胞死亡。Hsp40是一种分子伴侣，它引导Hsp70与疾病相关蛋白相互作用，并将它们在折叠、聚集和淀粉样蛋白形成的途径之间进行划分。Prion是一种感染性蛋白质，它会聚集成一种自我延续的类淀粉样蛋白状态，与神经退化有关。对酵母蛋白的研究已经提供了许多关于伴侣蛋白在淀粉样蛋白纤维形成中的作用的基本细节。在初步研究中，我们开发了一些检测方法来监测Hsp40在调节淀粉样蛋白形成和毒性方面的作用。本文提出的研究旨在确定异常的Prion生物发生导致细胞死亡的机制。此外，我们还试图确定不同Hsp40催化的Pron组装的特定步骤。最后，我们将确定I型和II型Hsp40亚型的结构和功能特征，这些亚型说明了它们在Prion生物发生中的作用。从这些研究中获得的数据将定义Hsp40在淀粉样蛋白形成中的作用规则，并确定治疗构象疾病的靶点。 构象疾病是一种神经退行性疾病，其中淀粉样纤维状异常折叠蛋白的积累通过未知的机制导致痴呆和细胞死亡。从拟议的研究中获得的数据将定义Hsp40在调节淀粉样蛋白形成和毒性方面的功能规则，并确定治疗构象疾病的靶点。