Integrin regulation of vascular function in Alzheimer's disease

项目摘要/摘要 该项目旨在了解控制血管和血脑的分子机制。 阿尔茨海默病(AD)的屏障功能及其与AD病理生理学的关系。广告研究已经 最近发现血管功能障碍是与认知相关的疾病的中心标志 损害，并积极调节神经炎性和淀粉样蛋白负荷在临床前模型和 病人。然而，阿尔茨海默病血管功能障碍的分子调控机制仍然有限。我们发现 在内皮细胞和周细胞中高表达的整合素CD49a是由转化诱导的 生长因子转化生长因子与AD(全基因组相关研究)及CD49a调控相关 在临床前模型中，表达影响AD的病理生理学。因此我们假设CD49a 血管内皮细胞表达调控阿尔茨海默病血管功能 TGFb与血管淀粉样变性有关，与AD的病理生理和认知负相关。 在我们初步数据的指导下，我们建议通过以下目标来解决我们的假设： 目的：探讨CD49a如何调节血脑屏障功能。 目的：检测血管内皮细胞中TGFb与CD49a的关系。 目的3：探讨内皮细胞CD49a在阿尔茨海默病发病机制中的作用。 总而言之，我们提议的研究将产生广泛的影响：a)破译细胞特定的作用 CD49a在血脑屏障功能中的作用；b)确定CD49a具有下游的有害作用途径 TGFb在AD血管病理中的作用；c)证实CD49a和血管功能障碍在AD发病中的作用 AD的病理生理学，以及d)强调靶向CD49a在AD和其他疾病中的治疗潜力 神经血管疾病。

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.