Understanding the role of the cerebral microvasculature in brain aging

项目摘要/摘要 衰老是脑血管、心血管疾病发生发展的主要危险因素之一。 和神经退行性疾病，导致老年人长期残疾和死亡。老化-- 相关的血管细胞进行性结构和功能衰退会导致血管功能障碍，例如 脑血流量减少。虽然血管系统是衰老最重要的目标之一，但它不是 明确是累积的血管病变还是衰老导致血管功能障碍。整体的长期 该项目的目标是阐明衰老和脑低灌注相关的脑部时间变化。 脉管系统。我们将检验大脑低灌流加剧衰老相关损害的假说 线粒体功能障碍促进了血脑屏障的完整性。为了检验我们的总体假设，我们 提出了两个具体目标。我们将使用年轻的和年老的，男性和女性的mito-Dendra2表达和野生 在拟议的研究中对小鼠进行分型。双侧颈总动脉狭窄(BCAS)将用于模拟 脑低灌注症。血管线粒体的治疗潜力将使用线粒体进行测试。 靶向四肽。将使用双光子显微镜来确定低灌注率是如何加剧的 体内与衰老相关的血脑屏障功能障碍，以绘制脑血管系统和血管线粒体动力学图 实时的。我们的研究将与免疫荧光研究、基于发现的蛋白质组学相补充 接近，和西方印迹。这项拟议的研究将揭示衰老和脑灌流不足是如何影响 内皮线粒体，并将阐明可能导致衰老相关病理的机制 比如阿尔茨海默氏症。

PROJECT SUMMARY/ABSTRACT Aging is one of the major risk factors for the development and progression of cerebrovascular, cardiovascular, and neurodegenerative diseases, contributing to long-term disability and mortality in the elderly. Aging- associated progressive structural and functional decline of vascular cells lead to vascular dysfunction such as decreased cerebral blood flow. While the vasculature is one of the most important targets of aging, it is not clear whether accumulating vascular pathologies or aging drives vascular dysfunction. The overall long-term goal of this project is to elucidate aging, and brain hypoperfusion-associated temporal changes in the cerebral vasculature. We will test the hypothesis that brain hypoperfusion exacerbates aging-associated compromised blood-brain-barrier integrity facilitated by mitochondrial dysfunction. To test our overall hypothesis, we proposed two specific aims. We will use young and old, male, and female mito-Dendra2 expressing and wild type mice in the proposed studies. Bilateral common carotid artery stenosis (BCAS) will be used to mimic cerebral hypoperfusion. The therapeutic potential of vascular mitochondria will be tested using a mitochondria targeted tetrapeptide. Two-photon microscopy will be used to determine how hypoperfusion exacerbates aging-associated BBB dysfunction in vivo, to map the brain vasculature, and vascular mitochondrial dynamics real time. Our studies will be complemented with immunofluorescence studies, discovery-based proteomics approach, and Western blot. The proposed research will reveal how aging and cerebral hypoperfusion affect endothelial mitochondria, and will elucidate mechanisms that might contribute to aging-related pathologies such as Alzheimer’s disease.