Tau-mediated chromatin regulation and neurodegeneration

Tau 介导的染色质调节和神经退行性变

• 批准号: 8319393
• 负责人: Bess Frost
• 金额: $ 5.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319393
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Autopsy; Biochemical; Biological; Brain; Cell Cycle; Chromatin; Chromatin Structure; Chromatin Structure Alteration; Complex; Data; Degenerative Disorder; Dementia; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Genetic; Genetic Models; Health; Human; Individual; Laboratories; Longevity; Mediating; Mediator of activation protein; Mitotic; Modeling; Molecular Genetics; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathogenesis; Patients; Play; Regulation; Role; Specificity; System; Tauopathies; Techniques; Toxic effect; Transgenic Mice; Transgenic Organisms; Work; abnormally phosphorylated tau; base; brain tissue; cell type; design; fly; genetic manipulation; histone modification; in vivo; insight; mouse model; neurotoxicity; novel therapeutics; polyglutamine; progressive neurodegeneration; research study; tau Proteins; tau expression

DESCRIPTION (provided by applicant): The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. The simple genetic model of tauopathy in Drosophila melanogaster recapitulates many key features of these diseases, including progressive neurodegeneration and aberrant tau phosphorylation. Furthermore, oxidative stress and cell cycle activation in post- mitotic neurons are key mediators of tau-induced neurodegeneration in humans and Drosophila models of tauopathy. Genetic, biochemical, and neuropathological techniques will be used to investigate the role of tau in the control of chromatin structure and determine the influence of chromatin changes on neurodegeneration. The proposed experiments will identify the types of histone modifications and chromatin complexes that occur due to tau expression in Drosophila. If we produce compelling evidence that tau mediates neurotoxicity through global chromatin alterations, our work will provide significant insight into the pathogenesis of tauopathies, including AD, and will suggest new therapeutic strategies for the disorders PUBLIC HEALTH RELEVANCE: The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. We propose to study tau-induced chromatin alterations in a Drosophila melanogaster model of AD.

描述（由申请人提供）：微管相关蛋白 tau 是阿尔茨海默病 (AD) 的病理标志，阿尔茨海默病是最常见的痴呆形式，以及二十多种其他神经退行性疾病，统称为“tau 病”。目前还没有针对 AD 或其他 tau蛋白病的疾病缓解疗法。果蝇 tau 蛋白病的简单遗传模型概括了这些疾病的许多关键特征，包括进行性神经变性和异常 tau 磷酸化。此外，有丝分裂后神经元中的氧化应激和细胞周期激活是人类和果蝇 tau 病模型中 tau 诱导的神经变性的关键介质。将利用遗传学、生化和神经病理学技术来研究tau蛋白在控制染色质结构中的作用，并确定染色质变化对神经退行性变的影响。拟议的实验将确定果蝇中由于 tau 表达而发生的组蛋白修饰和染色质复合物的类型。如果我们提供令人信服的证据证明 tau 通过整体染色质改变介导神经毒性，我们的工作将为包括 AD 在内的 tau 病的发病机制提供重要见解，并为这些疾病提出新的治疗策略 公共健康相关性：微管相关蛋白 tau 是阿尔茨海默病 (AD) 的病理标志，阿尔茨海默病是最常见的痴呆症，以及二十多种其他神经退行性疾病，统称为“tau 病”。目前还没有针对 AD 或其他 tau蛋白病的疾病缓解疗法。我们建议在 AD 果蝇模型中研究 tau 诱导的染色质改变。