Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury

衰老和缺血性损伤中的脑血管线粒体功能

• 批准号: 10693320
• 负责人: Daniel Tyrrell
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693320
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Bilateral; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Carotid Stenosis; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Coupled; Data; Dementia; Disease; Elderly; Excision; Exhibits; FPR1 gene; Faculty; Genetic; Glucose; Goals; Health; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Knockout Mice; Knowledge; Mediating; Mentors; Michigan; Mitochondria; Modeling; Molecular; Mus; Nerve Degeneration; Neurobiology; Oxidative Phosphorylation; Oxygen; Parkin; Pathology; Pathway interactions; Pattern; Persons; Positioning Attribute; Prevalence; Proteins; Reporter; Research; Research Personnel; Research Proposals; Risk; Rotenone; Specimen; Spermidine; Testing; Training; Transgenic Mice; Vascular Dementia; Vascular Diseases; age related; aged; blood damage; career; cell type; cerebral hypoperfusion; cerebrovascular; cognitive enhancement; cognitive function; conditional knockout; dementia risk; experience; formyl peptide; genetic approach; human old age (65+); improved; ischemic injury; member; mitochondrial dysfunction; mouse model; novel; pharmacologic; preservation; skills; vascular cognitive impairment and dementia; young adult

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.

项目概要/摘要 这项研究计划的制定是为了让候选人 Daniel Tyrrell 博士具备知识， 成功过渡到独立教职职位的经验和技能。拟议的研究 将研究老年人患血管疾病风险增加的机制。血管病理学 高达 80% 的阿尔茨海默病 (AD) 患者存在大脑问题，血管性痴呆位居第二 领先于 AD 的痴呆症。泰瑞尔博士将得到他的导师丹尼尔·戈德斯坦博士和丹尼尔·戈德斯坦博士的指导。 Michael Wang 以及密歇根阿尔茨海默病研究中心成员的帮助 各个领域的专家将为 Tyrrell 博士的培训做出贡献。泰瑞尔博士发现大脑 老年小鼠血管有线粒体功能障碍导致 STING-IL-6 增加的证据 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过程中的认知功能。因此， 目标 1 将确定与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 自然衰老过程中以及血管性痴呆模型中的血脑屏障和认知功能 脑灌注不足。目标 2 将研究脑血管炎症如何影响 BBB 和认知 衰老血管性痴呆模型中的功能。泰瑞尔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敲除小鼠外，线粒体功能增强的小鼠 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衰老过程中的认知功能，从而使自己脱颖而出 从他的导师那里得到帮助，并允许他在检查 VCID 方面发展前沿的独立职业生涯。