Hyperphosphorylated tau and the molecular mechanisms of tauopathy

过度磷酸化的 tau 蛋白和 tau 蛋白病的分子机制

基本信息

批准号：
10447253
负责人：
Min-Hao Kuo
金额：
$ 133.79万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447253
关键词：
Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic American Animals Apolipoprotein E Apolipoproteins Apoptosis Automobile Driving Biochemical Biological Assay Brain Cell Death Cell Survival Cell physiology Cells Cholesterol Cholesterol Homeostasis Clinical Dementia Deposition Development Disease Drug Prescriptions Enabling Factors Frontotemporal Lobar Degenerations Future Goals Hemeproteins Higher Order Chromatin Structure Homeostasis Hydroxycholesterols Impaired cognition Inflammation Lead Legitimacy Link Lipoproteins Modeling Modification Molecular Nerve Degeneration Nervous System Physiology Neuraxis Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oxidation-Reduction Oxygen Oxygenases Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Persons Phosphorylation Pick Disease of the Brain Progressive Supranuclear Palsy Protein Conformation Protein Isoforms Proteins Proteomics Recombinants Regulation Research Risk Factors System Tauopathies Text Therapeutic Toxic effect Trans-Activators abnormally phosphorylated tau cell injury cell killing chronic traumatic encephalopathy clinically significant cytotoxic cytotoxicity design drug development drug discovery druggable target empowered endoplasmic reticulum stress extracellular heme a hyperphosphorylated tau new therapeutic target novel therapeutics prion-like response spatiotemporal tau Proteins tau aggregation tau-1 trait translational study transmission process

项目摘要

Hyperphosphorylated tau and the molecular mechanisms of tauopathy Tauopathies are neurodegenerative disorders sharing the common pathology of the tau protein in the central nervous system. The most prominent tauopathy is Alzheimer’s disease (AD) that affects nearly 6 million Americans and more than 30 million people worldwide. Animal and cell studies demonstrated that soluble, oligomeric hyperphosphorylated tau is toxic to cells, and can transmit in a prion-like fashion in the brain. However, how hyperphosphorylation converts tau into a cytotoxic species, and how hyperphosphorylated tau exerts its cytotoxicity are unclear. As such, development of efficacious tauopathy therapeutics remains a formidable challenge. This R01 project aims to use a recombinant hyperphosphorylated tau (p-tau) as the model to examine the molecular mechanisms underlying tauopathies. Specifically, we wish to answer two major questions: how does hyperphosphorylated tau damage or kill cells? And what makes tau a cytotoxic species? We will perform proteomics studies to identify targets of p-tau that may lead to the realization of novel druggable targets for future therapeutics design. We will also pinpoint the phosphorylatable residues of the tau protein that, upon modification, drive the genesis and transmission of a pathogenic species. Finally, we have found that the formation of cytotoxic p-tau fibrils is subjected to the regulation of the ApoE lipoprotein and of selective metabolites of cholesterol. Biochemical and cell studies are to be performed to unravel the molecular details, which will facilitate our understanding of how different ApoE alleles contribute to the development of Alzheimer’s disease, as well as how cholesterol metabolism is mechanistically linked to this devastating disease.

高磷酸化的tau和tauopathy的分子机制陶氏病是神经退行性疾病，共享中央tau蛋白的常见病理神经系统。最杰出的tauopathy是阿尔茨海默氏病（AD），影响近600万美国人和全球超过3000万人。动物和细胞研究表明，可溶寡聚的高磷酸化tau对细胞有毒，并且可以在大脑中以风雨状的方式传播。然而，高磷酸化如何将TAU转化为细胞毒性物种，以及热磷酸化的Tau如何执行其细胞毒性尚不清楚。因此，有效的tauopathy疗法的发展仍然是一种强大的挑战。这个R01项目旨在使用重组的高磷酸化tau（p-tau）作为检查模型 aupathies的分子机制。具体来说，我们想回答两个主要问题：过度磷酸化会损害或杀死细胞吗？是什么使Tau成为细胞毒性物种？我们将表演蛋白质组学研究以识别P-TAU的靶标，这可能导致实现新的可药物靶标的未来治疗设计。在修饰，驱动致病物种的起源和传播。最后，我们发现细胞毒性P-TAU原纤维的形成受到apoE脂蛋白的调节和选择性的调节胆固醇的代谢产物。要进行生化和细胞研究以揭示分子细节，这将有助于我们对不同的APOE等位基因如何促进阿尔茨海默氏症的发展的理解疾病，以及胆固醇代谢如何机械地与这种毁灭性疾病联系起来。