Hyperphosphorylated tau as drug target

过度磷酸化的 tau 蛋白作为药物靶点

• 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
• 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' 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

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）：阿尔茨海默氏病（AD）是最常见的痴呆症，目前有500万美国人。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和几种其他破坏性神经退行性疾病统称为tau蛋白病，其中tau蛋白变得病理性过度磷酸化并聚集成神经元细胞中的神经元缠结（NFT）。由此产生的神经元死亡和认知缺陷导致AD和其他tau蛋白病患者的神经变性的进展。发现抑制形成或溶解预先形成的缠结的小化学物质是一种有吸引力的策略，可以减轻甚至逆转AD的进展。然而，迄今为止，所有据称的tau聚集抑制剂都是通过靶向非病理性、未磷酸化的tau而发现的。此外，动物研究表明，缠结可以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在临床上是有害的。这些争议的原因之一是缺乏一种有效的方法，产生过度磷酸化的tau蛋白的基础和翻译研究。我们已经开发了一种系统，通过该系统可以在E.杆菌使用过度磷酸化的重组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。这个探索性的R21项目将实现三个主要目标。首先，我们将研究GSK 3 <$-磷酸化tau蛋白如何在体外形成聚集体的分子细节。其次，我们将产生并比较与阿尔茨海默病相关的不同激酶产生的tau亚型。第三，使用GSK 3？- 磷酸化的tau，我们将建立一个药物筛选试验，并启动一项试点研究，这将导致发现小化合物，增强或抑制过度磷酸化的tau形成聚集体的倾向。新奇事物和展望。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高度磷酸化的tau蛋白。第一次，tau聚集的药物筛选将用病理学相关的同种型进行，以鉴定聚集增强剂和抑制剂。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，最终将导致发现新的治疗方案和策略。 公共卫生相关性：阿尔茨海默病目前袭击了500多万美国人，给这个国家带来了巨大的经济，情感和社会负担。在这项资助中，我们将使用一种新的ZAC技术来产生与阿尔茨海默氏症和其他几种神经退行性疾病的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一种新的靶标来筛选调节过度磷酸化tau聚集倾向的化合物，这最终可能导致延迟或停止阿尔茨海默病患者认知障碍的特定治疗方案。