Hyperphosphorylated tau as drug target

过度磷酸化的 tau 蛋白作为药物靶点

基本信息

批准号：
8093789
负责人：
Min-Hao Kuo
金额：
$ 18.14万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8093789
关键词：
Alzheimer&apos s Disease American Animals Biological Assay Caring Catalysis Cells Cellular Stress Cessation of life Characteristics Chemicals Cognitive deficits Country Craniocerebral Trauma Dementia Deposition Disease Disease Progression Drug Delivery Systems Emotional Employee Strikes Enhancers Escherichia coli Family Foundations Goals Grant Impaired cognition In Vitro Lead Link Metabolic syndrome Methods Microtubules Molecular NIH Program Announcements Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons New Territories Patients Phosphorylation Phosphotransferases Pilot Projects Post-Translational Protein Processing Preclinical Drug Evaluation Prevention Protein Isoforms Proteins Recombinant Proteins Recombinants Regimen Research Screening procedure System Tauopathies Techniques Therapeutic Time Validation base cardiovascular risk factor cost cytotoxic drug discovery hyperphosphorylated tau inhibitor/antagonist new technology novel novel therapeutics paired helical filament polymerization small molecule small molecule libraries tau Proteins tau aggregation tau-1 translational study

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most prevalent form of dementia that strikes 5 million Americans currently. Without effective prevention or therapeutics, the number of AD patients 65 years or older is projected to reach 13.5 million in 2050, with care costs exceeding 1 trillion dollars per year. AD and several other devastating neurodegenerative disorders are collectively known as tauopathies in which the tau protein becomes pathologically hyperphosphorylated and aggregates into the neurofibrillary tangles (NFT) in neuron cells. The resultant neuronal death and cognitive deficits lead to the progression of neurodegeneration of AD and other tauopathy patients. Discovering small chemicals that inhibit the formation of, or dissolve the pre-formed tangles is an attractive strategy that may mitigate or even revert the progression of AD. However, all of the purported tau aggregation inhibitors thus far have been discovered by targeting the non-pathological, unphosphorylated tau. Furthermore, animal studies suggested that the tangles may exert a protective function by sequestering the cytoplasmic hyperphosphorylated tau molecules. Accordingly, chemicals that liberate hyperphosphorylated tau from the tangles may actually be detrimental clinically. One of the reasons underlying these controversies is the lack of an efficient method that produces hyperphosphorylated tau protein for basic and translational studies. We have developed a system by which the tau protein phosphorylated by the GSK3¿ kinase can be effectively produced and purified in E. coli. Using the hyperphosphorylated recombinant tau protein as the target for drug discovery, pathophysiologically relevant therapeutic strategies can be established. This exploratory R21 project will achieve three major goals. Firstly, we will investigate the molecular details of how GSK3¿-phosphorylated tau forms the aggregate in vitro. Secondly, we will produce and compare tau isoforms resulting from different kinases that have been linked to Alzheimer's Disease. Thirdly, using the GSK3¿-phosphorylated tau, we will establish a drug screening assay and launch a pilot study that will lead to the discovery of small compounds that enhance or inhibit the propensity of hyperphosphorylated tau to form aggregates. Novelties and outlook. This R21 grant is an exploratory project in which we use a novel technology to produce hyperphosphorylated tau protein. For the first time, drug screen for tau aggregation will be conducted with a pathologically relevant isoform to identify both aggregation enhancers and inhibitors. By exploring these new territories, this project will lay a firm foundation for full-fledged basic and translational studies that eventually will lead to the discovery of novel therapeutic regimen and strategy. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease strikes more than 5 million Americans currently and imposes tremendous economical, emotional, and societal burdens to this country. In this grant, we will use a novel ZAC technique to produce hyperphosphorylated tau protein that is intimately linked to the progression of Alzheimer's and several other neurodegenerative diseases. We will use this protein as a novel target to screen for compounds that modulate the propensity of hyperphosphorylated tau to aggregate, which eventually may lead to a specific therapeutic regimen that delays or stops the cognitive impairment of Alzheimer's Disease patients.

描述（由申请人提供）：阿尔茨海默病 (AD) 是目前影响 500 万美国人的最常见的痴呆症，如果没有有效的预防或治疗方法，预计到 2050 年，65 岁或以上的 AD 患者人数将达到 1350 万。每年的护理费用超过 1 万亿美元，AD 和其他几种破坏性神经退行性疾病统称为 tau 蛋白病，其中 tau 蛋白发生病理性过度磷酸化并聚集。神经元细胞中的神经原纤维缠结 (NFT) 所导致的神经元死亡和认知缺陷会导致 AD 和其他 tau 病患者的神经退行性疾病的进展，发现抑制预先形成的缠结形成或溶解的小化学物质是一个有吸引力的研究。然而，迄今为止所有所谓的 tau 聚集抑制剂都是通过针对非病理性、此外，动物研究表明，缠结可能通过隔离细胞质过度磷酸化的 tau 分子来发挥保护功能，因此，从缠结中释放过度磷酸化 tau 的化学物质实际上可能是不健康的，这些争议的原因之一是缺乏。一种生产超磷酸化 tau 蛋白用于基础和转化研究的有效方法的研究我们开发了一种系统，通过该系统可以生产 tau 蛋白。被 GSK3 磷酸化¿使用高度磷酸化的重组 tau 蛋白作为药物发现的靶标，可以建立病理生理学相关的治疗策略，该探索性 R21 项目将实现三个主要目标。 GSK3 的详细信息?? -磷酸化 tau 在体外形成聚集体。其次，我们将产生并比较与阿尔茨海默氏病相关的不同激酶产生的 tau 亚型。第三，使用 GSK3¿ -磷酸化 tau，我们将建立一种药物筛选试验并启动一项试点研究，该研究将导致发现增强或抑制过度磷酸化 tau 形成聚集体倾向的小化合物。这项 R21 资助是一个探索性项目。我们使用一种新技术来生产过度磷酸化的 tau 蛋白，这是我们首次使用病理相关的同工型来进行 tau 聚集的药物筛选，以鉴定这两种蛋白。通过探索这些新领域，该项目将为全面的基础和转化研究奠定坚实的基础，最终将导致新的治疗方案和策略的发现。公共健康相关性：目前有超过 500 万美国人患有阿尔茨海默病，给这个国家带来了巨大的经济、情感和社会负担。在这笔资助中，我们将使用一种新型 ZAC 技术来生产与病情进展密切相关的过度磷酸化 tau 蛋白。我们将使用这种蛋白质作为新靶点来筛选调节过度磷酸化 tau 聚集倾向的化合物，这最终可能导致阿尔茨海默氏症和其他几种神经退行性疾病的发生。延缓或阻止阿尔茨海默病患者认知障碍的特定治疗方案。