Hsp40 and conformational disease

Hsp40 与构象疾病

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：构象疾病是神经退行性疾病，其中淀粉样蛋白异常折叠蛋白的淀粉样蛋白样形式的积累会通过未知机制引起痴呆和细胞死亡。 HSP40是分子伴侣，可将HSP70与疾病相关的蛋白质相互作用，并在折叠，聚集和淀粉样蛋白形成的途径之间进行分配。王室是与神经变性相关的自我延长淀粉样蛋白状态的传染蛋白。对酵母pr的研究为淀粉样蛋白纤维形成中的伴侣功能提供了许多基本细节。在初步研究中，我们开发了许多测定方法，以监测调节淀粉样蛋白形成和毒性的HSP40作用。本文提出的研究旨在定义异常prion生物发生会导致细胞死亡的机制。此外，我们试图确定由不同的HSP40催化的prion装配中的特定步骤。最后，我们将确定I型和II型HSP40子类型的结构和功能特征，该子类型指定其在prion生物发生中的作用。从这些研究中获得的数据将定义淀粉样蛋白形成中HSP40功能的规则，并确定治疗构象疾病的治疗靶标。构象疾病是一种神经退行性疾病，其中像淀粉样蛋白形式形式的异常折叠蛋白的形式的积累通过未知机制导致神经毒素和细胞死亡。从拟议的研究中获得的数据将定义HSP40功能的规则，以调节淀粉样蛋白形成和毒性，并确定治疗构象疾病的治疗靶标。