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：
8423028
负责人：
Dennis J Thiele
金额：
$ 31.83万
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423028
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.

描述（由申请人提供）：神经元细胞对蛋白质毒性高度敏感，神经退行性疾病如亨廷顿舞蹈病、阿尔茨海默病、帕金森病和朊病毒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、加工和周转中发挥作用，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质伴侣表达升高的潜在治疗作用。人类热休克转录因子 1 (HSF1) 协调激活许多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的基因的基础表达和诱导表达，这表明 HSF1 是神经退行性疾病药物干预的一个有吸引力的靶标。在本申请中，我概述了两个具体目标，重点关注新型小分子和调节蛋白的表征，这些目标可以为增强蛋白伴侣表达的药理学干预提供基础。在第一个具体目标中，我概述了旨在了解新型小分子 HSF1A 详细作用机制的实验，HSF1A 能够通过激活人类 HSF1 协调诱导蛋白伴侣表达。在第二个具体目标中，我概述了在纹状体细胞培养物、亨廷顿病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果蝇模型中评估 HSF1A 和结构相关分子功能的实验。这些研究将提供关于新型小分子的关键机制信息，作为协调提高蛋白质伴侣表达并改善与亨廷顿病和其他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的潜在治疗方法。