Activators of Nrf2 Translation in Alzheimer's Disease

阿尔茨海默病中 Nrf2 翻译的激活剂

• 批准号: 9267399
• 负责人: SALIM MERALI
• 金额: $ 7.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267399
• 关键词: Alzheimer disease prevention; Alzheimer' s Disease; Amyloid beta-Protein; Antioxidants; Biological Assay; Biosensor; Brain; Cell Line; Deposition; Drug Metabolic Detoxication; Elements; Enhancers; Enzymes; Gene Expression; Genes; Goals; Knowledge; Libraries; Mediating; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Open Reading Frames; Oxidative Stress; Pharmacology; Phase; Play; Production; Property; Proteins; Reporting; Role; Structure; Synapses; System; Testing; Therapeutic; Translations; antioxidant enzyme; base; cytotoxicity; design; disorder prevention; extracellular; in vivo; neuroprotection; novel; nuclear factor-erythroid 2; oxidative damage; pharmacophore; prevent; public health relevance; response; screening; sensor; small molecule; transcription factor

 DESCRIPTION (provided by applicant): This study is designed to screen potent activators of nuclear factor-erythroid 2 related factor 2 (Nrf2) translation for the treatment or prevention of Alzheimer's disease (AD). Nrf2 regulates the expression of most genes involved with the intrinsic antioxidant response and it has been widely reported with in vivo studies, that activatio of this transcription factor has the potential to ameliorate the progression of Alzheimer's disease. Most known activators of Nrf2 act indirectly by preventing its cytoplasmic degradation mediated by Kelch like ECH-associated protein 1 (Keap1). We recently found a novel regulatory mechanism of Nrf2 at the level of protein translation, and were able to create a biosensor to detect activators of Nrf2 translation. We propose testing this sensor to detect Nrf2 translational activators in 5040 natural-derived compounds library. After screening a library using this assay, those compounds found to activate Nrf2 translation will be examined in secondary screen for anti-AD activity. Our aim is to identify novel compounds that activate Nrf2 in cells lines involved with AD.

 描述（由适用提供）：本研究旨在筛选核因子 - 刺2相关因子2（NRF2）翻译的潜在激活剂，以治疗或预防阿尔茨海默氏病（AD）。 NRF2调节大多数与内在抗氧化剂反应有关的基因的表达，并且通过体内研究已广泛报道，该转录因子的活化有可能改善阿尔茨海默氏病的进展。 NRF2的最著名活化剂通过防止kelch介导的ECH相关蛋白1（KEAP1）介导的细胞质降解而间接起作用。我们最近在蛋白质翻译水平上发现了NRF2的新调节机制，并能够创建一个生物传感器来检测NRF2翻译的激活剂。我们建议对该传感器进行测试，以检测5040个天然衍生化合物库中的NRF2翻译激活剂。使用此测定法筛选库后，将在二级屏幕中检查发现激活NRF2翻译的这些化合物是否进行抗AD活性。我们的目的是识别激活涉及细胞系中NRF2的新型化合物 与广告。