Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury

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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.