Vascular Contributions to Enriched Rehabilitation in Hypertension

项目总结/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 通过确定康复影响卒中后认知功能的作用和血管机制进行研究 高血压是VCID和卒中患者的主要共病疾病。 中心假设是，丰富的康复可以防止严重的进行性卒中后认知功能障碍。 通过恢复成熟的脑源性神经元， 神经营养因子（BDNF）依赖性血管营养偶联。为了验证这一假设， 包含两个具体的目的，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）BDNF系统在ER介导的血管恢复中的作用， 高血压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，并暴露于标准外壳 条件或康复干预与环境富集和达到训练的组合， 5周和4周随访。认知和感觉运动功能结局将通过以下方式进行评估： 行为测试（新的物体识别，y-迷宫，猫步，和单颗粒达到任务）的短期和长期- 术语记忆/学习以及爪运动和步态的运动学分析。各种分子 方法，包括免疫组织化学，将被用来确定潜在的介质的血管生成和 MCAO后对ER的恢复反应的神经营养成分。脑源性神经营养因子是一种很有前途的 VCID研究的目标。内皮细胞特异性的shRNA沉默方法将被用来研究这种作用。 脑源性神经营养因子在ER恢复反应中的作用。申请人将完成本提案中概述的实验 在她的赞助商Adviye Ergul博士的指导下，在病理学和实验室医学系， 南卡罗来纳州医科大学。申请人计划利用技术技能和专业知识 她在奖学金培训期间获得的发展，过渡到初级教师职位，重点是 翻译VCID研究。申请人的长期职业目标是最终发展和维持一个 独立的研究计划，这将有助于我们的关键作用的基本知识， 在康复干预措施中，应加强对血管系统的保护，以减轻心脑血管疾病的负担。

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.