Vascular Injury and Recovery in Diabetic Ischemic Stroke

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This Diversity Supplement support is for Ms. Mia Edgerton in the laboratory of Dr. Adviye Ergul at the Medical University of South Carolina. Ms. Edgerton is a motivated and curious aspiring black scientist, whose goal is to become a knowledgeable independent investigator in the field of biomedicine. Ms. Edgerton will utilize her training and skills to obtain a high-ranked post-doctoral position, and ultimately lead her own research team in the future. To achieve these goals, Ms. Edgerton needs to acquire additional technical skills, enhance professional skills, and develop a robust academic profile. The objective of the parent grant (RF1NS083559-07) is to address the vast knowledge gap in the poor understanding of the impact and mechanisms by which increased hemorrhagic transformation (HT) occurs and influences the restorative and regenerative processes within the neurovascular networks leading to post-stroke cognitive impairment (PSCI) in diabetes. While clinically it is known that women suffer more from poor outcomes and PSCI. Furthermore, the inadequate inclusion of female animals in preclinical stroke research has further deepened this gap. Thus, the proposal focuses on stroke recovery in females and tests the hypothesis that toll like receptor (TLR)4 has a dual role in amplified vascular injury and compromised vascular restoration in females with diabetes. Based on our preliminary evidence that there is pathological neurovascular (NVU) remodeling and endothelial mesenchymal transition (EndMT) in the brains of diabetic female rats after stroke, Aim 2 of the parent grant tests the hypothesis that sustained eTLR4 activation due to HT mediates EndMT resulting in loss of NVU integrity and poor recovery in diabetes in females. The resistance of female BMVECs to cell death may also signify senescence. In this diversity supplement proposal, we will take an in vitro approach to address this gap in knowledge while providing a solid training platform for the applicant. The overarching hypothesis is that BMVPCs of female origin will be more susceptible to the development of senescence under diabetic conditions, and this response occurs in a TLR4 and/or endothelin (ET-1) dependent manner. We further hypothesize that this increase in senescence and associated secretory profile (SASP) will dysregulate the restorative, contractile, and immune-modulatory properties of BMVPCs. This training program will enhance Ms. Edgerton’s research skills and develop a solid understanding of preclinical vascular cognitive impairment (VCID) and stroke recovery research by providing detailed knowledge on brain microvascular pericyte pathophysiology while developing practical skill sets. She will also receive additional mentorship from a diverse research team and trainings to ensure she is fully equipped for her future career opportunities as an independent investigator.