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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：
7882166
负责人：
Dennis J Thiele
金额：
$ 33.69万
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/7882166
关键词：
Activator Appliances Alzheimer&apos s Disease Animal Model Binding Biochemical Brain Cell Culture Techniques Cell Death 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）：神经元细胞对蛋白质毒性高度敏感，神经变性疾病如亨廷顿氏病、阿尔茨海默氏病、帕金森氏病和朊病毒性疾病与不适当折叠或聚集的蛋白质的存在有关。蛋白质伴侣在蛋白质的正确折叠、加工和周转中起作用，并用于保护细胞免受蛋白质毒性。与蛋白质错误折叠相关的神经变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。人热休克转录因子1（HSF1）协调激活许多基因的基础和诱导型表达，这些基因编码蛋白伴侣和其他保护细胞免受应激和细胞死亡的蛋白质，这表明HSF1是神经退行性疾病中药理学干预的有吸引力的靶标。在本申请中，我概述了两个具体的目标，重点是表征新的小分子和调节蛋白，可以提供一个基础的药理学干预，以提高蛋白伴侣表达。在第一个具体目标中，我概述了了解一种新型小分子HSF1A的详细作用机制的实验，这种小分子能够通过激活人HSF1协同诱导蛋白伴侣表达。在第二个具体目标中，我概述了在纹状体细胞培养、亨廷顿病的皮质纹状体大鼠脑切片模型和与polyQ蛋白聚集相关的神经退行性疾病的果蝇模型中评估HSF 1A和结构相关分子的功能的实验。这些研究将为新型小分子作为潜在的治疗方法提供关键的机制信息，以协调提高蛋白伴侣表达并改善与亨廷顿病和其他人类神经退行性疾病相关的蛋白质聚集缺陷。公共卫生关系：神经变性疾病如亨廷顿氏病、阿尔茨海默氏病、帕金森氏病和肌萎缩侧索硬化症与错误折叠和聚集蛋白的存在有关。本申请中提出的研究旨在表征新的化学物质和基因，这些化学物质和基因可以作为开发治疗方法的基础，以改善与人类神经退行性疾病相关的蛋白质折叠缺陷。