Tau-mediated chromatin regulation and neurodegeneration

Tau 介导的染色质调节和神经退行性变

基本信息

批准号：
8197962
负责人：
Bess Frost
金额：
$ 5.13万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2010-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197962
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos 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

项目摘要

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）：微管相关的蛋白质TAU是阿尔茨海默氏病（AD）的病理标志，是痴呆症的最常见形式，以及其他二十多种神经退行性疾病，统称为“ tauopathies”。目前尚无针对AD或其他tauopathies的疾病改良治疗方法。果蝇中的Tauopathy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，有丝分裂神经元中的氧化应激和细胞周期活化是tau诱导的人类和tauopathy果蝇模型中神经变性的关键介体。遗传，生化和神经病理学技术将用于研究TAU在控制染色质结构中的作用，并确定染色质变化对神经变性的影响。提出的实验将确定由于果蝇中Tau表达引起的组蛋白修饰和染色质复合物的类型。如果我们产生令人信服的证据表明TAU通过全球染色质改变介导神经毒性，我们的工作将为包括AD在内的陶氏病的发病机理提供重大见解，并将提出有关疾病的新治疗策略公共卫生相关性：微管相关的蛋白质TAU是阿尔茨海默氏病（AD）的病理标志，是痴呆症的最常见形式，以及其他二十多种神经退行性疾病，统称为“ tauoparties”。目前尚无针对AD或其他tauopathies的疾病改良治疗方法。我们建议研究AD果蝇模型中TAU诱导的染色质改变。