Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury

项目总结/摘要 这项研究计划是为了让候选人丹尼尔泰瑞尔博士掌握知识， 经验和技能，以成功地过渡到一个独立的教师职位。拟议研究 将研究为什么老年人患血管疾病的风险增加的机制。血管病理学 大脑存在于高达80%的阿尔茨海默氏病（AD）患者中，血管性痴呆是第二位 导致痴呆症仅次于AD。泰瑞尔博士将从他的导师丹尼尔戈尔茨坦博士和博士的指导。 迈克尔·王和密歇根阿尔茨海默病研究中心成员的协助下，沿着 来自不同领域的专家将为泰瑞尔博士的培训做出贡献。泰瑞尔博士发现大脑 老年小鼠的血管有线粒体功能障碍的证据，导致STING-IL-6增加 炎症和血脑屏障破坏。血管对认知功能影响的机制 衰老中的损伤和痴呆（VCID）仍不清楚。因此，本研究的目的是 确定脑血管线粒体功能障碍如何影响衰老中的认知功能。因此，我们认为， 目的1将确定年龄相关的脑血管线粒体自噬和线粒体功能障碍如何影响脑血管疾病的发生。 在自然衰老过程中和在由血管性痴呆诱导的模型中的血脑屏障和认知功能 脑灌注不足目的2将研究脑血管炎症如何影响BBB和认知功能， 在血管性痴呆伴衰老模型中的功能。Tyrrell博士将使用新型线粒体自噬报告小鼠， 除了使用细胞类型特异性条件性敲除小鼠之外还具有增强的线粒体功能的小鼠 模型和药理学方法。泰瑞尔博士将获得技术和科学神经生物学 专业知识，以研究血脑屏障的完整性和认知功能的老化，以区分自己 从他的导师，并允许他发展一个尖端的独立职业生涯，在检查VCID。

PROJECT SUMMARY/ABSTRACT This research proposal has been developed to equip the candidate, Dr. Daniel Tyrrell, with knowledge, experience, and skills to successfully transition into an independent faculty position. The proposed research will examine mechanisms of why older adults are at increased risk of vascular disease. Vascular pathology in the brain is present in up to 80% of people with Alzheimer’s disease (AD) and vascular dementia is the second leading dementia behind AD. Dr. Tyrrell will have guidance from his mentors, Dr. Daniel Goldstein and Dr. Michael Wang, and assistance from members of the Michigan Alzheimer’s Disease Research Center along with experts in diverse fields who will contribute to Dr. Tyrrell’s training. Dr. Tyrrell has discovered that cerebral blood vessels in aged mice have evidence of mitochondrial dysfunction leading to increased STING-IL-6 inflammation and blood-brain barrier breakdown. The mechanisms of vascular contributions to cognitive impairment and dementias (VCID) in aging remain unclear. Therefore, the objective of this study is to determine how cerebrovascular mitochondrial dysfunction impacts cognitive function in aging. Hence, Aim 1 will determine how age-related cerebrovascular mitophagy and mitochondrial dysfunction impacts the blood-brain barrier and cognitive function during natural aging and in a model of vascular dementia induced by cerebral hypoperfusion. Aim 2 will examine how cerebrovascular inflammation impacts the BBB and cognitive function in a model of vascular dementia with aging. Dr. Tyrrell will employ novel mitophagy reporter mice and mice with enhanced mitochondrial function in addition to using cell-type specific conditional knockout mouse models and pharmacologic approaches. Dr. Tyrrell will acquire both technical and scientific neurobiology expertise in order to study blood-brain barrier integrity and cognitive function in aging to distinguish himself from his mentors and allow him to develop a cutting-edge independent career in examining VCID.