HSF1 as a therapeutic target in neurodegenerative disease

HSF1作为神经退行性疾病的治疗靶点

基本信息

批准号：
8220871
负责人：
Dennis J Thiele
金额：
$ 33万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220871
关键词：
Activator Appliances Alzheimer&apos s Disease Animal Model Binding Biochemical Brain Cell Culture Techniques Cell Death Cell model Cells Cellular Stress Chaperone Gene Characteristics Chemicals Complex Corpus striatum structure DNA Binding Defect Disease Drosophila genus Embryo Fibroblasts Gene Expression Genes Homo Human Huntington Disease Intervention Modeling Molecular Molecular Chaperones Molecular Machines Neurodegenerative Disorders Neurons Parkinson Disease Post-Translational Protein Processing Primary Lateral Sclerosis Process Proteins Rattus Research Role Slice Therapeutic Toxic effect Wild Type Mouse Yeasts base genetic regulatory protein heat shock transcription factor human Huntingtin protein in vivo monomer novel polyglutamine precursor cell prevent prion-based protein activation protein aggregate protein aggregation protein degradation protein folding protein misfolding public health relevance research study small molecule therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Neuronal cells are highly sensitive to proteo-toxicity and neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and prion-based disease are associated with the presence of inappropriately folded or aggregated proteins. Protein chaperones function in the proper folding, processing and turnover of proteins and serve to protect cells from proteo-toxicity. Experimental evidence in cellular and animal models of neurodegenerative diseases associated with protein misfolding strongly support a potential therapeutic role for elevated protein chaperone expression. The human Heat Shock Transcription Factor 1 (HSF1) coordinately activates both basal and inducible expression of many genes encoding protein chaperones and other proteins that protect cells from stress and cell death, suggesting that HSF1 is an attractive target for pharmacological intervention in neurodegenerative disease. In this application I outline two specific aims that focus on the characterization of novel small molecules and regulatory proteins that could provide a basis for pharmacological intervention to enhance protein chaperone expression. In the first Specific Aim I outline experiments to understand the detailed mechanism of action of a novel small molecule, HSF1A, capable of coordinately inducing protein chaperone expression through the activation of human HSF1. In the second Specific Aim I outline experiments to evaluate the function of HSF1A, and structurally related molecules, in striatal cell culture, a corticostriatal rat brain slice model of Huntington<s disease and in a fruit fly model of neurodegenerative disease associated with polyQ protein aggregation. These studies will provide critical mechanistic information on novel small molecules as potential therapeutic approaches to coordinately elevate protein chaperone expression and to ameliorate protein aggregation defects associated with Huntington<s disease and other human neurodegenerative diseases of protein misfolding. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and Amyotropic Lateral Sclerosis are associated with the presence of misfolded and aggregated proteins. The research proposed in this application aims to characterize novel chemicals and genes that could serve as a basis for the development of therapeutic approaches to ameliorate defects in protein folding associated with human neurodegenerative disease.

描述（由申请人提供）：神经元细胞对蛋白毒性和神经退行性疾病高度敏感，例如亨廷顿，阿尔茨海默氏症，帕金森氏症和基于普里奥的疾病与存在不当折叠或聚集的蛋白质有关。蛋白质伴侣在适当的折叠，加工和蛋白质周转中发挥作用，并保护细胞免受蛋白质毒性。与蛋白质错误折叠相关的神经退行性疾病的细胞和动物模型中的实验证据强烈支持蛋白伴侣表达升高的潜在治疗作用。人类热休克转录因子1（HSF1）协同激活许多编码蛋白伴侣和其他保护细胞免受压力和细胞死亡的蛋白质的基础和诱导表达，这表明HSF1是对神经退行性疾病的药理干预的有吸引力的靶标。在此应用中，我概述了两个特定的目的，该目标集中在新型小分子和调节蛋白的表征上，这些分子和调节蛋白可以提供药理干预以增强蛋白质伴侣表达的基础。在第一个特定的目的中，我概述了实验，以了解一种新型小分子HSF1A的详细作用机理，能够通过人类HSF1的激活协调诱导蛋白伴侣的表达。在第二个特定目的中，I概述了评估HSF1A和结构相关的分子在纹状体细胞培养中的功能，这是亨廷顿疾病的皮质纹状体大鼠脑切片模型以及与PolyQ蛋白聚集相关的神经退行性疾病的果蝇模型。这些研究将提供有关新型小分子的关键机械信息，作为潜在的治疗方法，可以协同升高蛋白质伴侣的表达并改善与亨廷顿疾病和其他人类蛋白质错误折叠的人类神经退行性疾病相关的蛋白质聚集缺陷。公共卫生相关性：神经退行性疾病，例如亨廷顿，阿尔茨海默氏症，帕金森氏症和肌动体侧性硬化症，与存在错误折叠和聚集的蛋白质有关。该应用中提出的研究旨在表征新型化学物质和基因，这些化学物质和基因可以作为发展与人类神经退行性疾病相关的蛋白质折叠缺陷的治疗方法的基础。