Age-related vascular cognitive impairment: role of endothelial senescence

年龄相关的血管认知障碍:内皮衰老的作用

基本信息

  • 批准号:
    10044293
  • 负责人:
  • 金额:
    $ 36.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

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.
项目概要/摘要 目前有超过5000万65岁以上的人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—— 引起的 VCID 尚不清楚,越来越多的证据表明 神经血管单元发挥着至关重要的作用。该提案的目的是阐明 衰老相关内皮功能障碍在认知障碍中的机制作用。这 中心假设是衰老主要促进大脑内皮细胞的衰老 随后的功能障碍,改变血管舒张介质的产生,损害 神经血管耦合反应,促进血脑屏障(BBB)破坏和 微血管稀疏。由此导致脑血流量(CBF)下降并增加 神经炎症会导致认知障碍。拟议的工作是新颖的 第一个证明衰老引起的内皮衰老是一个关键因素 VCID 的发病机制。结果可能会确定具体的机制和 揭示能够改善 CBF 和恢复学习的潜在疗法 记忆。提出以下目标:1)确定内皮衰老如何改变 神经血管耦合反应、CBF 和衰老认知。工作假设是 衰老诱导的内皮细胞 p16 依赖性细胞衰老程序的激活 损害血管舒张功能。据预测,衰老内皮细胞的消除 细胞,通过基因操作或通过衰老疗法将恢复神经血管 功能并改善老年小鼠的 CBF 和认知能力。 2)确定衰老如何改变 衰老过程中的微血管密度和血脑屏障完整性。工作假设是激活 内皮细胞中 p16 依赖性细胞衰老程序损害内皮屏障 功能并损害微循环网络的维护。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 老年小鼠的脑微血管密度。 3) 确定细胞间的异质性 衰老内皮细胞及其形态和功能 特征。总之,拟议的研究将确定一个基本机制 控制衰老引起的脑血管变化,最终导致认知障碍。

项目成果

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Anna Csiszar其他文献

Anna Csiszar的其他文献

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{{ truncateString('Anna Csiszar', 18)}}的其他基金

Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence
化疗引起的血管性认知障碍:内皮衰老的作用
  • 批准号:
    10323272
  • 财政年份:
    2021
  • 资助金额:
    $ 36.25万
  • 项目类别:
Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence
化疗引起的血管性认知障碍:内皮衰老的作用
  • 批准号:
    10539312
  • 财政年份:
    2021
  • 资助金额:
    $ 36.25万
  • 项目类别:
Age-related vascular cognitive impairment: role of endothelial senescence
年龄相关的血管认知障碍:内皮衰老的作用
  • 批准号:
    10671650
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
Age-related vascular cognitive impairment: role of endothelial senescence
年龄相关的血管认知障碍:内皮衰老的作用
  • 批准号:
    10453694
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
Age-related vascular cognitive impairment: role of endothelial senescence
年龄相关的血管认知障碍:内皮衰老的作用
  • 批准号:
    10222565
  • 财政年份:
    2020
  • 资助金额:
    $ 36.25万
  • 项目类别:
ANIMAL MODEL DEVELOPMENT AND BEHAVIORAL ASSESSMENT (AMD-BA) CORE
动物模型开发和行为评估 (AMD-BA) 核心
  • 批准号:
    10536647
  • 财政年份:
    2019
  • 资助金额:
    $ 36.25万
  • 项目类别:
ANIMAL MODEL DEVELOPMENT AND BEHAVIORAL ASSESSMENT (AMD-BA) CORE
动物模型开发和行为评估 (AMD-BA) 核心
  • 批准号:
    10077913
  • 财政年份:
    2019
  • 资助金额:
    $ 36.25万
  • 项目类别:
Microvascular mechanisms of neuroinflammation: role of Nrf2
神经炎症的微血管机制:Nrf2 的作用
  • 批准号:
    8748331
  • 财政年份:
    2014
  • 资助金额:
    $ 36.25万
  • 项目类别:
Vasoprotection by Caloric Restriction Mimetics in Aging
衰老过程中热量限制模拟物的血管保护作用
  • 批准号:
    8146105
  • 财政年份:
    2010
  • 资助金额:
    $ 36.25万
  • 项目类别:
Vasoprotection by Caloric Restriction Mimetics in Aging
衰老过程中热量限制模拟物的血管保护作用
  • 批准号:
    8320900
  • 财政年份:
    2010
  • 资助金额:
    $ 36.25万
  • 项目类别:

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