Targeting REV-ERB to treat Alzheimer's disease

靶向 REV-ERB 治疗阿尔茨海默病

• 批准号: 10675294
• 负责人: Thomas P Burris
• 金额: $ 198.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675294
• 关键词: Targeting; REV; ERB; treat; Alzheimer

Alzheimer's disease (AD) is a progressive neurodegenerative disease with clinical features that include memory loss, cognitive impairment and dementia. According to 2017 data from the Alzheimer's Association, AD is the 6th leading cause of death in the U.S. and will cost the nation $259 billion dollars this year. More than 5 million Americans currently live with the diagnosis of AD and it is expected to increase to as much as 16 million by 2050. Current treatments for AD have very limited efficacy and thus there is a significant need for improved pharmacological therapies. AD is characterized by the formation of senile plaques and neurofibrillary tangles in the grey matter of affected individuals. The senile plaques are composed of extracellular deposition of insoluble amyloid beta (Aβ) peptides that are typically associated with a wealth of microglia (brain resident macrophages) and astrocytes. It is generally recognized that the extracellular accumulation of Aβ is a key event the pathogenesis of AD. Inflammation induced by accumulation of Aβ is believed to be a crucial factor underlying the neural dysfunction and microglia and bone marrow derived phagocytes recruited to the plaques are fundamental to the pathogenesis of AD. We discovered that the REV-ERB nuclear receptors play a critical role in regulation of neuroinflammation and that pharmacological activation of REV-ERB effectively reduces neuroinflammation and improves cognitive function in a model of AD. The goal of this project is to develop optimized REV-ERB agonists that may be effective agents for reduction of neuroinflammation in treatment of Alzheimer's disease and, potentially, other neurodegenerative disorders associated with neuroinflammation.

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其临床特征包括 记忆力丧失，认知障碍和痴呆症。根据2017年的数据 协会，广告是美国第六大死亡原因，将使该国损失2590亿美元 年。目前有超过500万美国人居住着AD的诊断，预计将增加 到2050年到2050年多达1600万。当前的AD治疗效率非常有限，因此有一个 对改善药物疗法的重要需求。广告的特征是形成老年 受影响个体的灰质中的斑块和神经纤维缠结。老年斑块是 由通常相关的不溶性淀粉样β（Aβ）肽的细胞外沉积 大量的小胶质细胞（脑居民巨噬细胞）和星形胶质细胞。通常认识到 Aβ的细胞外积累是AD发病机理的关键事件。引起的炎症 据信，Aβ的积累是神经功能障碍和小胶质细胞和小胶质细胞的关键因素 衍生成斑块的骨髓衍生的吞噬细胞是AD发病机理的基础。我们 发现Rev-erb核接收器在调节神经炎症和 Rev-ERB的药物激活有效地减少了神经炎症并改善了认知 在AD模型中的功能。该项目的目的是开发优化的Rev-erb激动剂，可能是 在治疗阿尔茨海默氏病的治疗中，有效减少神经炎症的药物 与神经炎症相关的神经退行性疾病。