Inflammasome-based Alzheimer's disease therapy in the context of diabetes

糖尿病背景下基于炎症小体的阿尔茨海默病治疗

• 批准号: 10287353
• 负责人: Jayakrishna Ambati
• 金额: $ 40.37万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10287353
• 关键词: Accounting; Administrative Supplement; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapy; Award; Biochemical; Brain; Cognitive; Data; Dementia; Diabetes Mellitus; Diabetic Retinopathy; Disease; Endocrinologist; Epidemiology; Hyperglycemia; Hyperinsulinism; Immunologist; Impaired cognition; Inflammasome; Insulin Resistance; Kinetics; Laboratories; Link; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Outcome; Parents; Risk Factors; Role; Signal Transduction; Testing; United States National Institutes of Health; Work; base; comorbidity; improved; inhibitor/antagonist; mouse model; neuroinflammation; novel; prevent; progressive neurodegeneration

Scope of Work / Abstract This Administrative Supplement proposal is to investigate the role of inflammasome signaling in models of Alzheimer's disease (AD) complicated by diabetes mellitus (DM). AD is a progressive neurodegeneration accounting for 60-70% of all the dementia worldwide. DM, the metabolic syndrome responsible for a variety of complications including diabetic retinopathy (the subject of the parent proposal), is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. Numerous epidemiologic analyses have identified DM as a significant risk factor and comorbidity for AD. In addition, DM and AD share inflammasome activation as pathomechanisms, and each entity has independently been shown to be responsive to inflammasome inhibition. We propose to test the overall hypothesis that inflammasome inhibition reduces neuroinflammation and improves cognitive outcomes in mouse AD models that are complicated by the co-morbidity of DM. To accomplish this, we will critically assess the spatial and temporal kinetics of inflammasome activation in the brain in combined DM/AD models. In addition, we will test whether the presence of DM affects the efficacy of inflammasome inhibition on cognitive outcomes of AD mouse models. As such, this supplement request focused on AD is within the scope of the active parent NIH award and has the potential to stimulate new studies for examining novel molecular and biochemical mechanisms of inflammasome activation in AD in the presence of metabolic disorders. We predict that establishing inflammasome as a key link between DM and AD will stimulate additional activity on the part of endocrinologists, immunologists, and neurobiologists thereby leading to progress in deciphering and potentially treating AD and related dementias complicated by DM. This supplement will also enable our laboratory to develop a focus on AD and related dementias by generating additional experimental data that can be leveraged to submit new proposals focused directly on AD and related dementias.

工作范围/摘要 本行政补充提案旨在研究炎性体信号传导在 阿尔茨海默病（AD）并发糖尿病（DM）模型。 AD是一个进步的 神经退行性疾病占全世界痴呆症的 60-70%。 DM，代谢 导致多种并发症的综合征，包括糖尿病视网膜病变（糖尿病视网膜病变的主题） 家长提案），其特点是高血糖、高胰岛素血症和胰岛素抵抗。 许多流行病学分析已确定 DM 是一个重要的危险因素和合并症 对于AD。此外，DM 和 AD 都有炎症小体激活的病理机制，并且各自都有 实体已被独立证明对炎性体抑制有反应。我们建议 检验炎症小体抑制可减少神经炎症的总体假设 改善小鼠 AD 模型的认知结果，该模型因共病而变得复杂 DM。为了实现这一目标，我们将严格评估空间和时间动力学 DM/AD 联合模型中大脑中炎症小体的激活。此外，我们将测试是否 DM 的存在影响炎症小体抑制对 AD 认知结果的功效 鼠标模型。因此，此针对 AD 的补充请求属于主动的范围之内。 母体 NIH 奖项，有潜力刺激新分子的新研究 AD 存在代谢物时炎症小体激活的生化机制 失调。我们预测炎症小体将成为 DM 和 AD 之间的关键环节 将刺激内分泌学家、免疫学家和 神经生物学家从而在破译和潜在治疗 AD 及相关疾病方面取得了进展 DM 并发痴呆。该补充品还将使我们的实验室能够开发一个重点 通过生成可利用的额外实验数据来研究 AD 和相关痴呆症 提交直接针对 AD 和相关痴呆症的新提案。