Integrin regulation of vascular function in Alzheimer's disease

整合素对阿尔茨海默病血管功能的调节

• 批准号: 10901016
• 负责人: Antoine Louveau
• 金额: $ 60.55万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901016
• 关键词: Address; Age Months; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Behavioral; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrovascular system; Chemicals; Cognition; Cognitive; Collagen; Data; Dementia; Development; Disease; Early Onset Alzheimer Disease; Electron Microscopy; Endothelial Cells; Endothelium; Excision; Extravasation; Fibrinogen; Functional disorder; Genetic; Goals; Histology; Impaired cognition; In Vitro; Infiltration; Inflammation; Integrin Binding; Integrins; Intrathecal Injections; Knowledge; Late Onset Alzheimer Disease; Mediating; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Patients; Pericytes; Pre-Clinical Model; Preventive; Proteins; Regulation; Research; Risk Factors; Role; Signal Transduction; TGFB1 gene; Testing; Therapeutic; Transforming Growth Factors; Up-Regulation; Vascular Diseases; abeta accumulation; amyloid pathology; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; cognitive function; cytokine; genome wide association study; glial activation; glymphatic function; glymphatic system; hyperphosphorylated tau; improved; in vivo; inhibitor; mouse model; neuroinflammation; neurovascular; novel therapeutics; overexpression; pharmacologic; social; tau Proteins; transcriptomics; β-amyloid burden

PROJECT SUMMARY/ABSTRACT This project aims at understanding the molecular mechanisms governing vascular and blood brain barrier function in Alzheimer’s disease (AD), and their involvement in AD pathophysiology. AD research has recently identified vascular dysfunction as a central hallmark of the disease correlating with cognitive impairment, and actively mediating the neuroinflammatory and amyloid burden in pre-clinical models and patients. However, the molecular mechanisms regulating vascular disfunction in AD remains limited. We found that the integrin CD49a, highly expressed in endothelial cells and pericytes and induced by the transforming growth factor TGF, is associated with AD (genome wide associated studies) and that modulation of CD49a expression impact the pathophysiology of AD in a pre-clinical model. We therefore hypothesize that CD49a expression by blood endothelial cells regulates vascular function in AD, mediates the deleterious effects of TGFb on vascular amyloidosis and negatively contribute to AD pathophysiology and cognition. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim1: Determine how CD49a regulates blood brain barrier function. Aim2: Test the relationship between TGFb and CD49a in endothelial cells. Aim 3: Test the contribution of endothelial CD49a in the pathophysiology of Alzheimer’s disease. Collectively, our proposed studies will have a broad impact by: a) decipher the cell specific role of CD49a in blood brain barrier function; b) identify CD49a has a downstream pathway for the deleterious effects of TGFb on vascular pathology in AD; c) assert the role of CD49a and vascular dysfunction in the pathophysiology of AD, and d) highlight the therapeutic potential of targeting CD49a in AD and other neurovascular disorders.

项目摘要/摘要 该项目旨在了解有关血管和血脑的分子机制 阿尔茨海默氏病（AD）中的障碍功能及其参与AD病理生理学。广告研究有 最近确定血管功能障碍是该疾病与认知相关的核心标志 损害，并在临床前模型和 患者。但是，在AD中调节血管功能的分子机制仍然有限。我们发现 在内皮细胞和周细胞中高表达的整合素CD49A，由转化引起 生长因子TGF与AD（基因组广泛的研究）和CD49A的调节有关 表达影响临床前模型中AD的病理生理。因此，我们假设CD49A 血液内皮细胞的表达调节AD中的血管功能，介导 TGFB对血管淀粉样变性和负面病理生理学和认知有效。 在我们的初步数据的指导下，我们建议使用以下目的解决我们的假设： AIM1：确定CD49A如何调节血脑屏障功能。 AIM2：测试内皮细胞中TGFB和CD49A之间的关系。 AIM 3：测试内皮CD49A在阿尔茨海默氏病的病理生理学中的贡献。 总的来说，我们提出的研究将通过以下方式产生广泛的影响：a）破译细胞的特定作用 CD49A血液脑屏障功能； b）识别CD49A具有有害影响的下游途径 TGFB在AD中的血管病理学； c）主张CD49A和血管功能障碍在 AD的病理生理学，D）突出靶向AD和其他靶向CD49A的治疗潜力 神经血管疾病。