Understanding the role of the cerebral microvasculature in brain aging

了解脑微血管在大脑衰老中的作用

• 批准号: 10719620
• 负责人: Ibolya Rutkai
• 金额: $ 58.87万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719620
• 关键词: 3-Dimensional; Affect; Aging; Alzheimer' s Disease; Arteries; Autophagocytosis; Bilateral; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Brain; Brain Mapping; Cardiovascular Diseases; Cardiovascular Pathology; Carotid Stenosis; Cell physiology; Cells; Cephalic; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chimeric Proteins; Common carotid artery; Complement; Complex; Data; Dementia; Deterioration; Development; Disease; Elderly; Endothelial Cells; Endothelium; Equilibrium; Exposure to; Female; Functional disorder; Goals; Health; Heart; Hyperemia; Immunofluorescence Immunologic; Impaired cognition; Lead; Link; Maps; Methods; Mitochondria; Morphology; Mus; Nature; Neurodegenerative Disorders; Organ; Pathology; Peptides; Perfusion; Process; Production; Proteins; Proteome; Proteomics; Quality Control; Reactive Oxygen Species; Rejuvenation; Research; Risk Factors; Role; Skeletal Muscle; Slice; Structure; Surface; Testing; Therapeutic; Time; Tissues; Vascular Diseases; Vascular Endothelium; Vascularization; Western Blotting; Wild Type Mouse; aged; aging brain; blood-brain barrier disruption; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; cerebral hypoperfusion; cerebral microvasculature; cerebrovascular; density; disability; functional decline; hypoperfusion; improved; in vivo; male; mitochondrial dysfunction; mitochondrial membrane; mortality; neurovascular coupling; protein expression; reconstruction; respiratory; restoration; senescence; sham surgery; two photon microscopy; vascular bed

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.

项目概要/摘要 衰老是脑血管、心血管、心血管等疾病发生和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- 血管细胞相关的进行性结构和功能衰退导致血管功能障碍，例如 脑血流量减少。虽然脉管系统是衰老最重要的目标之一，但它并不是 明确累积的血管病变或衰老是否会导致血管功能障碍。整体长期来看 该项目的目标是阐明衰老和大脑灌注不足相关的大脑时间变化 脉管系统。我们将检验以下假设：大脑灌注不足会加剧与衰老相关的受损 线粒体功能障碍促进血脑屏障完整性。为了检验我们的总体假设，我们 提出了两个具体目标。我们将使用年轻人和老年人、男性和女性 mito-Dendra2 表达和野生 在拟议的研究中类型小鼠。双侧颈总动脉狭窄（BCAS）将用于模拟 脑灌注不足。将使用线粒体测试血管线粒体的治疗潜力 靶向四肽。双光子显微镜将用于确定灌注不足如何加剧 与衰老相关的体内 BBB 功能障碍，绘制脑血管系统和血管线粒体动力学图 即时的。我们的研究将得到免疫荧光研究、基于发现的蛋白质组学的补充 方法和蛋白质印迹。拟议的研究将揭示衰老和脑灌注不足如何影响 内皮线粒体，并将阐明可能导致衰老相关病理的机制 例如阿尔茨海默病。