Age-related vascular cognitive impairment: role of endothelial senescence

项目摘要/摘要 超过5000万65岁以上的人目前受到血管疾病的影响 认知障碍和痴呆(VCID)。尽管衰老的具体机制-- 诱导的VCID尚不清楚，有越来越多的证据表明 神经血管单位起着至关重要的作用。这项建议的目的是澄清 衰老相关的内皮功能障碍在认知损害中的机制作用。这个 中心假说是衰老主要促进大脑内皮细胞的衰老 随后的功能障碍，改变血管扩张介质的产生，损害 神经血管偶联反应，促进血脑屏障(BBB)破坏和 微血管疏松。由此导致的脑血流量(CBF)下降和增加 神经炎症会导致认知障碍。拟议的工作是新颖的，因为它将是 第一个证明衰老诱导的内皮细胞衰老是一个关键因素 在VCID发病机制中起重要作用。结果可能会确定具体的机制和 揭示潜在的治疗方法，能够改善脑血流，恢复学习和 记忆。提出了以下目标：1)确定内皮细胞衰老是如何改变的 衰老过程中的神经血管偶联反应、脑血流和认知功能。工作假说是 增龄诱导内皮细胞p16依赖的细胞衰老程序的激活 会损害血管扩张功能。据预测，衰老的内皮细胞的消除 细胞，通过基因操作或感觉神经溶解疗法将恢复神经血管 能改善衰老小鼠的脑血流量和认知功能。2)确定衰老如何改变 增龄时微血管密度和血脑屏障完整性。工作假说是激活 内皮细胞中依赖p16的细胞衰老程序损害内皮屏障 并影响微循环网络的维持。据预测， 消除衰老细胞将恢复血脑屏障，减轻神经炎症并增加 老龄小鼠脑微血管密度。3)确定细胞间的异质性 衰老内皮细胞及其形态和功能 特点。总之，拟议的研究将确定一个基本的机制 管理衰老引起的脑血管变化最终导致认知障碍。

PROJECT SUMMARY/ ABSTRACT More than 50 million people over the age of 65 are currently affected by vascular cognitive impairment and dementia (VCID). Although the specific mechanisms for aging- induced VCID are not yet known, there is increasing evidence that alterations of the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of senescence-related endothelial dysfunction in cognitive impairment. The central hypothesis is that aging primarily promotes endothelial senescence in the brain and subsequent dysfunction, altering the production of vasodilator mediators, impairing neurovascular coupling responses, promoting blood-brain barrier (BBB) disruption and microvascular rarefaction. The resulting decline in cerebral blood flow (CBF) and increased neuroinflammation contribute to cognitive impairment. The proposed work is novel as it will be the first to demonstrate that aging-induced endothelial senescence is a critical contributing factor to the pathogenesis of VCID. The results will likely identify specific mechanisms and reveal potential therapies that are capable of improving CBF and restoring learning and memory. The following aims are proposed: 1) Determine how endothelial senescence alters neurovascular coupling responses, CBF and cognition in aging. The working hypothesis is that aging-induced activation of p16-dependent cellular senescence program in endothelial cells impairs vasodilator function. It is predicted that elimination of senescent endothelial cells, through genetic manipulation or through senolytic therapies will restore neurovascular function and improve CBF and cognition in aged mice. 2) Determine how senescence alters microvascular density and BBB integrity in aging. The working hypothesis is that activation of p16-dependent cellular senescence program in endothelial cells impairs endothelial barrier function and compromise the maintenance of the microcirculatory network. It is predicted that elimination of senescent cells will restore BBB, attenuating neuroinflammation and increase cerebromicrovascular density in aged mice. 3) Determine cellular heterogeneity among senescent endothelial cells in conjunction with their morphological and functional characteristics. Together, the proposed studies will identify a fundamental mechanism governing aging-induced cerebrovascular changes eventually leading to cognitive impairment.