Vascular Contributions to Enriched Rehabilitation in Hypertension

项目摘要/摘要 该项目旨在解决血管对认知障碍/痴呆(VCID)的贡献方面的差距 康复治疗对卒中后认知功能影响的作用及血管机制研究 损害是VCID的主要症状，高血压是VCID和卒中患者的主要共病。 中心假设是，丰富的康复可以防止中风后认知的深刻进行性 通过修复成熟的脑源性细胞损伤和改善高血压动物的功能结果 神经营养因子(BDNF)依赖的血管营养偶联。为了检验这一假设，该提案 包含两个特定的目的，以确定(1)ER对缺血性脑损伤后功能恢复的影响 高血压和(2)脑源性神经营养因子系统在内质网介导的血管功能恢复中的作用 高血压合并缺血性脑损伤。雄性和雌性自发性高血压大鼠(SHR)将经历 大脑中动脉闭塞(MCAO)或假手术，并暴露在标准住房中 环境丰富和REACH训练相结合的条件或康复干预 分别随访5周和4周。认知和感觉运动功能结果将通过以下方式评估 行为测试(新颖的物体识别、Y形迷宫、T台步和单颗粒触达任务) 除了爪子运动和步态的运动学分析外，术语记忆/学习。各种分子 包括免疫组织化学在内的方法将被用来确定血管生成和血管生成的潜在介体。 大脑中动脉阻塞后ER恢复反应的神经营养成分。BDNF是一种很有前途的机制 VCID研究的目标。一种内皮细胞特异性shRNA沉默的方法将被用来研究这一作用 BDNF在ER恢复反应中的作用。申请者将完成本建议书中概述的实验 在她的赞助人Adviye Ergul博士的指导下， 南卡罗来纳医科大学。应聘者计划利用技术技能和专业知识 她在团契培训期间获得的发展，过渡到初级教员职位，重点是 翻译VCID研究。申请人的长期职业目标是最终发展和保持一种 独立研究计划，将有助于我们对关键作用的基础知识 为了减轻心脑血管疾病的负担，在康复干预中加入血管系统。

Project Summary/Abstract This project is designed to address a gap in vascular contributions to cognitive impairment/dementia (VCID) research by determining the role and vascular mechanisms by which rehabilitation impacts post-stroke cognitive impairment, a principal VCID, in hypertension, the leading comorbid disease in patients with VCID and stroke. The central hypothesis is that enriched rehabilitation prevents profound progressive post-stroke cognitive impairment and improves functional outcomes in hypertensive animals via restoration of mature brain-derived neurotrophic factor (BDNF)-dependent vasotrophic coupling. In order to test this hypothesis, the proposal contains two specific aims to determine (1) the impact of ER on functional recovery after ischemic brain injury in hypertension and (2) the role of the BDNF system in the vascular contributions of ER-mediated recovery after ischemic brain injury in hypertension. Male and female spontaneously hypertensive rats (SHRs) will undergo either middle cerebral artery occlusion (MCAO) or sham procedure and be exposed to either standard housing conditions or a rehabilitation intervention with a combination of environmental enrichment and reach training for 5 weeks and 4 weeks of follow up. Cognitive and sensorimotor functional outcomes will be assessed by behavioral tests (novel object recognition, y-maze, Catwalk, and single-pellet reach task) for short- and long- term memory/learning in addition to kinematic analysis of paw movements and gait. A variety of molecular methods, including immunohistochemistry, will be used to identify potential mediators of the angiogenic and neurotrophic components of the recovery response to ER following MCAO. BDNF is one promising mechanistic target in VCID research. An endothelial cell-specific shRNA silencing approach will be used to examine the role of BDNF in the recovery response to ER. The applicant will complete the experiments outlined in this proposal under the guidance of her sponsor, Dr. Adviye Ergul, in the Department of Pathology & Laboratory Medicine at the Medical University of South Carolina. The applicant plans to utilize the technical skills and professional development she gains during the fellowship training to transition to a junior faculty position with a focus on translational VCID research. The long-term career goal of the applicant is to ultimately develop and maintain an independent research program that will contribute to our fundamental knowledge of the critical role of the vasculature in rehabilitation interventions in order to reduce the burden of cardio/cerebrovascular diseases.