使用伽马分泌酶调节剂的显性遗传 AD 网络体外试验-猫眼课题宝

使用伽马分泌酶调节剂的显性遗传 AD 网络体外试验

批准号：

9795379

负责人：

Steven Lee Wagner

金额：

$0.0万

依托单位：

VA SAN DIEGO HEALTHCARE SYSTEM

依托单位国家：

美国

项目类别：

财政年份：

2017

资助国家：

美国

项目状态：

已结题

起止时间：

2017-06-01 至 2021-05-31

来源：

https://reporter.nih.gov/project-details/9795379

关键词：

Affect Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Amyloid beta-Protein Animal Model Award Axon Axonal Transport Biological Markers Brain-Derived Neurotrophic Factor Cell model Cells Clinical Trials Collaborations DNA Sequence Alteration Development Diagnosis Digit structure Disease Disease Progression Dose Early Endosome Early Onset Familial Alzheimer&apos s Disease Effectiveness Enrollment Evaluation Event Failure Fibroblasts Functional disorder Funding Generations Goals Human In Vitro Inherited Investigational Drugs Late Onset Alzheimer Disease Lead Link MAPT gene Measures Mediating Methods Modeling Mus Mutation Neurofibrillary Tangles Neurons No-Observed-Adverse-Effect Level Non-Steroidal Anti-Inflammatory Agents Onset of illness Pathology Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Prevention trial Primary Prevention Process Production Rattus Rodent Rodent Model Secure System Testing Therapeutic Therapeutic Index Toxic effect Toxicity Tests Toxicology United States National Institutes of Health Veterans abeta accumulation axonopathy base clinical candidate cohort drug development efficacy study efficacy testing extracellular gamma secretase good laboratory practice hyperphosphorylated tau improved in vivo induced pluripotent stem cell inhibitor/antagonist mutant mutation carrier neuropathology non-demented nonhuman primate novel patient population preclinical evaluation presenilin-1 resistance mutation response safety testing side effect small molecule success tau Proteins

中文摘要

翻译

阿尔茨海默病(AD)是由细胞外斑块组成的神经病理学定义 β-淀粉样蛋白(Aβ42)和由过度磷酸化形式的微管相关蛋白tau。Aβ积聚和tau蛋白过度磷酸化被认为是导致全面阿尔茨海默病神经病理的关键事件。在这里，我们建议一组独特的新型小分子药物伽玛-的体外综合分析分泌酶调节剂(GSM)以进一步探索AD的治疗方法。这项提案将重点放在在人类神经元上测试旨在阻止Aβ42-的最佳先导临床候选药物- 相关病理类型AD。我们的首要假设是旨在扰乱生产的GSM疗法 Of Aβ42将是治疗先兆或早期AD以及散发性AD的有效方法晚发性阿尔茨海默病。该项目的目标是验证人类神经元中的靶向参与精选的病人。

英文摘要

Alzheimer’s disease (AD) is defined neuropathologically by extracellular plaques composed of β-amyloid (Aβ42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. Aβ accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose comprehensive in vitro analysis of a unique set of novel small molecule drugs known gamma- secretase modulators (GSMs) to further explore AD therapeutics. This proposal will focus on testing an optimal lead clinical candidate for efficacy in human neurons aimed at halting Aβ42- related pathologies AD. Our overarching hypothesis is GSM therapy aimed to disrupt production of Aβ42 will be an efficacious treatment approach for prodromal or early AD, as well as sporadic late-onset AD. The goal of this project is to validate target engagement in human neurons from selected patients.

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