Identifying new tau targeted therapeutics: a drug repurposing approach

确定新的 tau 靶向疗法：药物再利用方法

• 批准号: 8815851
• 负责人: Brian C. Kraemer
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815851
• 关键词: Advanced Development; Affect; Alzheimer' s Disease; Amyloid; Automobile Driving; Basic Science; Behavioral; Biological Assay; Biological Markers; Biological Models; Blast Cell; Brain; Brain Injuries; Caenorhabditis elegans; Cell Culture Techniques; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Data; Defect; Deposition; Development; Diagnosis; Disease; Disease model; Dopamine D2 Receptor; Dopamine Receptor; Dose; Drug usage; Effectiveness; Elderly; Endothelial Cells; Exhibits; FDA approved; Figs - dietary; Functional disorder; Future; Genetic; Goals; Health; Healthcare; Healthcare Systems; Human; Intervention; Lead; Lesion; Libraries; Mediating; Methods; Modeling; Mus; Nematoda; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathology; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacopoeias; Phenotype; Population; Pre-Clinical Model; Preclinical Drug Evaluation; Preclinical Testing; Publishing; Recording of previous events; Research; Research Project Grants; Risk; Role; Route; Senile Plaques; Staging; Symptoms; System; Tauopathies; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Translating; Translations; Traumatic Brain Injury; Veterans; Work; age related; base; bench to bedside; chronic traumatic encephalopathy; disability; drug discovery; effective therapy; follow-up; human disease; man; meetings; mild traumatic brain injury; mouse model; neurodegenerative dementia; neuropathology; neurotoxicity; novel; novel therapeutics; premature; prevent; progressive neurodegeneration; public health relevance; research clinical testing; screening; small molecule; targeted treatment; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; therapeutic target; translational study

DESCRIPTION (provided by applicant): The amyloid plaques made of Ab peptide and neurofibrillary tangles made of abnormal tau protein define the neuropathology of Alzheimer's disease. Many diverse studies support an initiating role for amyloid in Alzheimer's disease. However, these findings also clearly demonstrate both that the presence of tau is required for amyloid mediated neuronal dysfunction and that pathological tau protein causes neurodegeneration. Furthermore, pathological tau, including neurofibrillary tangles, characterizes the neuropathology of blast induced traumatic brain injury, chronic traumatic encephalopathy, and other related tauopathies. Traumatic brain injury is increasingly prevalent in the Veteran population. Both aging related changes and brain injury dramatically increase the risk for neurodegenerative dementia disorders. Thus it is imperative we develop treatments that can quickly bridge the gap between bench and bedside. Development of pharmacological interventions for tau mediated neurodegeneration is the long-term goal of this research project. Our drug discovery strategy employs an integrated approach aimed at expediting drug repurposing. Our previously published work demonstrated the effectiveness of these methods by screening a library of 1120 approved drugs to identify a single validated compound capable of ameliorating tau pathology in a transgenic mouse model of tauopathy. We now propose to extend this drug repositioning approach to a drug collection spanning most of the drugs with a history of clinical use (~5400 drugs). The objectives of this project are to: Identify compounds reducing tau aggregation in a transgenic C. elegans model of tauopathy and in a human cell culture model of tau aggregation; Prioritize hits based on their CNS penetration and identify dosing and routes of administration that modulate pathological tau in young mice; Use novel compounds identified above to intervene in symptomatic tauopathy mice. Completion of these studies will reveal FDA approved candidate drugs for use as tau targeted therapeutics for both Alzheimer's disease and blast induced traumatic brain injury, providing justification for the clinical testing of repurposed approved drugs for treatment of tauopathy disorders.

描述(由申请人提供)： 由抗体多肽组成的淀粉样斑块和由异常tau蛋白组成的神经纤维缠结定义了阿尔茨海默病的神经病理学。许多不同的研究支持淀粉样蛋白在阿尔茨海默病中的起始作用。然而，这些发现也清楚地表明，tau的存在是淀粉样蛋白介导的神经元功能障碍所必需的，也是病理性tau蛋白导致神经退行性变的原因。此外，病理性tau，包括神经原纤维缠结，是冲击波引起的创伤性脑损伤、慢性创伤性脑病和其他相关tau病的神经病理学特征。创伤性脑损伤在退伍军人中越来越普遍。与衰老相关的变化和脑损伤都极大地增加了神经退行性痴呆疾病的风险。因此，我们必须开发能够迅速弥合板凳和床边之间差距的治疗方法。开发tau介导的神经退行性变的药物干预是本研究项目的长期目标。我们的药物发现战略采用了一种旨在加快药物再利用的综合方法。我们之前发表的工作证明了这些方法的有效性，通过筛选1120种批准药物的库来确定能够改善tau病变转基因小鼠模型中tau病理的单一有效化合物。我们现在建议将这种药物重新定位方法扩展到涵盖大多数有临床使用历史的药物(约5400种药物)的药物收集。该项目的目标是：在转基因秀丽线虫的tau聚集性模型和在tau聚集性的人类细胞培养模型中确定减少tau聚集的化合物；基于它们的中枢神经系统渗透对HITS进行优先排序，并确定调节幼鼠病理tau的剂量和给药途径；使用上述新化合物来干预有症状的tau病小鼠。这些研究的完成将揭示FDA批准的用于治疗阿尔茨海默病和冲击性脑损伤的tau靶向治疗药物的候选药物，为临床测试用于治疗tau病障碍的重新用途的批准药物提供了理由。