Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury

项目摘要/摘要 这项研究提案是为了让候选人丹尼尔·泰雷尔博士掌握知识， 成功过渡到独立教职的经验和技能。拟议的研究 将研究老年人患血管疾病风险增加的机制。中国的血管病理学 高达80%的阿尔茨海默病(AD)患者存在大脑，其次是血管性痴呆 导致阿尔茨海默病的痴呆。泰瑞尔博士将得到他的导师丹尼尔·戈尔茨坦博士和丹尼尔·戈尔茨坦博士的指导。 Michael Wang和密歇根阿尔茨海默病研究中心成员的帮助下 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 老年小鼠的血管有证据表明线粒体功能障碍导致STING-IL-6增加 炎症和血脑屏障破坏。血管对认知的贡献机制 衰老过程中的损害和痴呆(VCID)仍不清楚。因此，这项研究的目的是 确定衰老过程中脑血管线粒体功能障碍对认知功能的影响。因此， 目标1将确定与年龄相关的脑血管有丝分裂和线粒体功能障碍如何影响 血管性痴呆模型中血脑屏障与自然衰老及认知功能的关系 脑低灌注症。目标2将研究脑血管炎症如何影响血脑屏障和认知能力 在血管性痴呆模型中随年龄增长的功能。泰瑞尔博士将利用新型的有丝分裂报告小鼠和 除了使用细胞型特异性条件基因敲除小鼠外，还具有增强线粒体功能的小鼠 模型和药理学方法。泰瑞尔博士将同时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在衰老中脱颖而出 并允许他在研究VCID方面发展一种尖端的独立职业生涯。

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.