Vascular Injury and Recovery in Diabetic Ischemic Stroke

糖尿病缺血性中风的血管损伤和恢复

• 批准号: 10541346
• 负责人: ADVIYE ERGUL
• 金额: $ 12.82万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541346
• 关键词: Acute; Address; Administrative Supplement; Alteplase; American; Animals; Attenuated; Blood Vessels; Brain; Brain hemorrhage; Cell Aging; Cell Death; Cerebrovascular system; Cicatrix; Clinical; Cognitive; Conditioned Reflex; Coupled; Development; Diabetes Mellitus; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Ensure; Enzymes; Female; Functional disorder; Funding; Future; Goals; Hemorrhage; Immune; Impaired healing; In Vitro; Inflammatory Response; Injury; Iron; Iron Chelation; Ischemic Stroke; Knowledge; Laboratories; Lead; Long-Term Care Nursing; MMP3 gene; Mediating; Mediator of activation protein; Medical; Mentorship; Mesenchymal; Metalloproteases; Modeling; Molecular; Outcome; Pathologic; Pathway interactions; Patients; Pericytes; Pharmacological Treatment; Phenotype; Population; Positioning Attribute; Postdoctoral Fellow; Process; Property; Rattus; Recovery; Recovery of Function; Research; Research Personnel; Resistance; Role; Scientist; Signal Transduction; Solid; South Carolina; Stroke; TLR4 gene; Technical Expertise; Testing; Therapeutic; Training; Training Programs; Transforming Growth Factor beta; Universities; Vascular Cognitive Impairment; Woman; acute stroke; base; brain endothelial cell; career; cerebral microvasculature; chronic stroke; diabetic; diabetic patient; diabetic rat; experience; functional outcomes; glycemic control; high risk; injury recovery; male; neuroprotection; neurorestoration; neurovascular; neurovascular unit; novel; novel therapeutic intervention; parent grant; physically handicapped; post stroke; post stroke cognitive impairment; pre-clinical; regenerative; repair function; restoration; senescence; sex; skills; stroke outcome; stroke recovery; vascular injury

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.

这项多样性补充支持是为米娅·埃杰顿女士提供的，她在阿德维耶·厄格尔博士的实验室 南卡罗来纳大学。埃杰顿女士是一位有上进心和好奇心、有抱负的黑人科学家，她的目标是 成为生物医学领域知识渊博的独立研究员。埃杰顿女士会利用她 培训和技能，以获得高级别的博士后职位，并最终领导自己的研究团队在 未来。为了实现这些目标，Edgerton女士需要获得更多的技术技能，加强 专业技能，并建立健全的学术形象。家长资助的目的(RF1NS083559-07) 就是要解决人们在对其影响和机制缺乏了解方面的巨大知识差距 出血转化增加(HT)发生并影响修复和再生过程 在导致糖尿病患者中风后认知障碍(PSCI)的神经血管网络内。虽然在临床上 众所周知，妇女更多地遭受不良结局和PSCI的痛苦。此外，不充分地纳入 雌性动物在临床前中风研究中进一步加深了这一差距。因此，该提案侧重于 女性中风的康复，并验证了Toll样受体(TLR)4在扩增的过程中具有双重作用的假设 女性糖尿病患者的血管损伤和受损的血管修复。根据我们的初步调查 病理性神经血管(NVU)重塑和内皮间质转化的证据 (EndMT)在中风后糖尿病雌性大鼠的大脑中，父母拨款的目标2检验了以下假设 羟色胺持续激活eTLR4介导EndMT导致NVU完整性丧失和恢复不良 女性患糖尿病。雌性BMVECs对细胞死亡的抵抗也可能意味着衰老。在这 多样性补充建议，我们将采取体外方法来解决这一知识差距，同时提供 为申请者提供坚实的培训平台。最重要的假设是，女性起源的BMVPC将是 在糖尿病条件下更容易发生衰老，这种反应发生在 TLR4和/或内皮素(ET-1)依赖。我们进一步假设，衰老的增加和 相关分泌谱(SASP)将失调恢复性、收缩和免疫调节 BMVPC的属性。这一培训计划将增强埃杰顿女士的研究技能，并为 了解临床前血管性认知障碍(VCID)和卒中康复研究 具备脑微血管周细胞病理生理学方面的详细知识，同时发展实用技能。她 还将接受来自不同研究团队的额外指导和培训，以确保她完全准备好 为她未来作为一名独立调查员的职业机会。