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; 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 这项行政补充提案是调查炎性体信号在 糖尿病（DM）复杂的阿尔茨海默氏病（AD）模型。广告是进步的 神经变性占全球所有痴呆症的60-70％。 DM，代谢 负责各种并发症在内的综合症，包括糖尿病性视网膜病（主题） 母体建议），其特征是高血糖，高胰岛素血症和胰岛素抵抗。 许多流行病学分析已确定DM是重要的危险因素和合并症 对于广告。此外，DM和AD共享炎症体激活作为致病力机制，并且 实体已独立地证明对炎症体抑制作用有反应。我们建议 为了检验总体假设，即炎性体抑制可减少神经炎症和 改善了鼠标广告模型中的认知结果 DM。为此，我们将批判性地评估 在组合DM/AD模型中，大脑中的炎症体激活。此外，我们将测试是否 DM的存在会影响炎性体抑制AD认知结果的功效 鼠标模型。因此，该补充请求的重点是广告的范围 父级NIH奖，并有可能刺激新研究以检查新分子 在代谢存在下，AD中炎性体激活的生化机制 疾病。我们预测，将炎症组确定为DM和AD之间的关键联系 将刺激内分泌学家，免疫学家和 神经生物学家因此，导致破译和潜在治疗AD和相关的进展 DM复杂的痴呆症。该补充剂还将使我们的实验室能够培养重点 通过生成可以利用的其他实验数据，在AD和相关痴呆症上 提交直接关注AD和相关痴呆症的新建议。