Vascular Injury and Recovery in Diabetic Ischemic Stroke

糖尿病缺血性中风的血管损伤和恢复

基本信息

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
项目类别：
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

项目摘要

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医学中心 Adviye Ergul 博士实验室的 Mia Edgerton 女士提供的。南卡罗来纳大学的埃哲顿女士是一位积极进取、充满好奇、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者后，埃哲顿女士将利用她。获得高级博士后职位的培训和技能，并最终领导自己的研究团队为了实现这些目标，埃杰顿女士需要获得额外的技术技能，增强能力。专业技能，并培养良好的学术形象家长补助金的目标 (RF1NS083559-07) 的目的是解决对影响和机制了解不足的巨大知识差距出血转化（HT）增加并影响恢复和再生过程在临床上，神经血管导致糖尿病中风后认知障碍（PSCI）。众所周知，女性更容易遭受不良结果和 PSCI 的影响。雌性动物的临床前中风研究进一步加深了这一差距，因此，该提案的重点是。女性中风恢复并测试了 Toll 样受体 (TLR)4 在放大中具有双重作用的假设根据我们的初步研究，女性糖尿病患者的血管损伤和血管修复受损。有证据表明存在病理性神经血管（NVU）重塑和内皮间质转化 (EndMT) 在糖尿病雌性大鼠中风后的大脑中，父母资助的目标 2 检验了以下假设：由于 HT 介导 EndMT 导致 eTLR4 持续激活，导致 NVU 完整性丧失和恢复不良女性 BMVEC 对细胞死亡的抵抗力也可能意味着衰老。多样性补充提案，我们将采取体外方法来解决这一知识差距，同时提供为申请人提供坚实的培训平台总体假设是女性出身的 BMVPC 将是在糖尿病条件下更容易出现衰老，并且这种反应发生在我们进一步发现这种衰老和/或内皮素（ET-1）依赖性的增加。相关分泌谱 (SASP) 会导致恢复性、收缩性和免疫调节失调该培训计划将提高 Edgerton 女士的研究技能并培养扎实的基础知识。通过提供对临床前血管性认知障碍 (VCID) 和中风恢复研究的理解有关脑微血管周细胞病理生理学的详细知识，同时培养实用技能。还将接受来自多元化研究团队的额外指导和培训，以确保她具备充分的能力为她未来作为独立调查员的职业机会。