Understanding the role of the cerebral microvasculature in brain aging

项目总结/摘要 衰老是脑血管、心血管、 和神经退行性疾病，导致老年人长期残疾和死亡。老化- 相关的血管细胞的进行性结构和功能下降导致血管功能障碍， 脑血流量减少虽然脉管系统是衰老最重要的目标之一，但它不是。 明确血管病变的积累或衰老是否会导致血管功能障碍。整体长远 本项目的目的是阐明衰老和脑灌注不足相关的大脑中的时间变化， 脉管系统我们将检验脑灌注不足会加重与衰老相关的脑损害的假设。 血脑屏障完整性促进线粒体功能障碍。为了验证我们的假设，我们 提出了两个具体目标。我们将使用年轻人和老年人，男性和女性mito-Dendra 2表达和野生型 小鼠在拟议的研究。双侧颈总动脉狭窄（BCAS）将用于模拟 脑灌注不足血管线粒体的治疗潜力将使用线粒体 靶向四肽。双光子显微镜将用于确定灌注不足如何加重 衰老相关的体内BBB功能障碍，以绘制脑血管和血管线粒体动力学 真实的时间。我们的研究将补充免疫荧光研究，发现为基础的蛋白质组学 方法和Western blot。这项拟议中的研究将揭示衰老和脑灌注不足如何影响 内皮线粒体，并将阐明机制，可能有助于衰老相关的病理 例如阿尔茨海默氏病。

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.