Examining Vascular Regulation Following Acute Stroke

描述(由申请者提供)：本次辅导式职业发展奖候选人的长期目标是：1)增加她在与中风相关的血管生理学方面的曝光率、经验和可信度；2)获得对制定康复研究长期学习计划至关重要的正式和非正式培训经验；以及3)执行和扩展她的综合培训计划，使其成为独立的研究职业，并提交R01申请。支持她长期目标的候选人的近期目标将集中在：1)更好地了解血管生理学(通过课程和实验室经验)，以了解急性中风可能发生的机械性血管变化；2)掌握为血流介导的扩张(FMD)、多普勒超声和专门的血管壁跟踪软件进行实验和数据分析的基本技能；3)了解中风康复早期的有氧运动如何降低血管功能障碍；4)收集结果和试点数据，以成为R01提交的独立调查者。 候选人将有机会获得的指导、培训计划和环境是强有力的，并将确保成功的职业发展。这一职业发展奖的导师拥有与候选人互补的背景和经验，他们致力于帮助她成功并实现她的目标。比林格博士的导师拥有NIH资助的经验和记录，发表过大量出版物，并有指导初级教职员工/研究人员的历史。每一位导师都为候选人走向独立的科学和事业发展做出了独特的贡献。Nudo博士是这位候选人的主要导师，他将帮助候选人了解大脑生理学、中风后发生的一连串脑细胞事件、勇气、为高影响力的期刊提交和NIH拨款改进科学写作技能，以及进行机械性的、假设驱动的研究。联合导师登格尔博士将帮助学习如何使用FMD技术，使用多普勒超声进行血管扫描，并使用电子血管壁跟踪软件解释结果。共同导师道恩博士将提供关于血管生理学、血流和自主神经控制的实验室经验和研究讨论。他将促进候选人和血管超声诊断师之间富有成效的学习环境。共同导师伍德博士将提供有关血管调节和桌面技术的实验室经验和指导，以确定与血流减少、缺氧和血管功能障碍相关的机制。比林格博士将在伍德的实验室里使用这种酶联免疫吸附试验技术来识别血浆中的促炎因子。共同导师Rmer博士将确保能够接触到中风患者群体并获得在医院(圣卢克脑研究所)进行实验的资源。她参与了几项临床试验，可以帮助候选人在招募、同意和退学方面采取方法和解决问题。 研究计划：慢性中风患者偏瘫肢体血流减少。更好地了解影响中风后血管调节的机械因素可能会导致创新的康复策略，从而减少残疾并改善功能结果。由于脑损伤，中风后会释放促炎标志物。促炎标记物在中风后24小时内进入外周血管系统。细胞因子(TNF-a、IL-6)和血管黏附分子(VCAM-1)是促炎标志物，当它们存在于血管系统中时，可以减少一氧化氮的产生和/或释放，一氧化氮是一种强有力的血管扩张剂。一氧化氮是血管扩张所必需的，以适应运动期间增加的血流量。尽管中风后人们的血管功能发生了变化，但试点工作表明，锻炼可以改善偏瘫肢体的血液流动。候选人将招募急性中风后的个体来检查促炎标志物和血管功能之间的关系(使用血流介导的扩张)。将对血浆样本进行分析，以定量确定血浆中促炎症标志物的数量。将使用多普勒超声和专门的血管壁跟踪软件来评估血管功能。在该项目最具创新性的方面，候选人还将探索有氧运动干预在中风康复中的作用。候选人认为，运动干预将下调促炎标志物的作用，并改善血管调节。候选人计划将这些实验的结果用作更大规模临床试验的试点数据。然而，在进行临床试验之前，了解促炎标志物和血管功能在卒中康复过程中的作用是重要的，也是必不可少的。

DESCRIPTION (provided by applicant): The candidate for this Mentored Career Development Award has as long-term goals to: 1) increase her exposure, experience and credibility in vascular physiology as it relates to stroke; 2) obtain formal and informal training experiences that are essential to developing a long-term plan of study in rehabilitation research; and 3) execute and expand her comprehensive training program into an independent research career and submit an R01 application. The candidate's immediate goals that support her long-term goals will be to focus on: 1) obtaining a better understanding of vascular physiology (through courses and lab experiences) to understand the mechanistic vascular changes that may occur as a result of an acute stroke; 2) acquiring the essential skills to conduct experiments and data analysis for flow-mediated dilation (FMD), Doppler ultrasound and the specialized, vascular wall tracking software; 3) understanding how aerobic exercise early in stroke rehabilitation reduces vascular dysfunction; and 4) gathering results and pilot data to become an independent investigator on an R01 submission. The mentorship, training plan and environment that the candidate will have access to are robust and will ensure successful career development. The mentors for this Career Development Award have the background and experience that is complementary to the candidate's and they are committed to helping her succeed and meet her goals. Dr. Billinger's mentors have experience and a track-record of NIH funding, numerous publications and a history of mentoring junior faculty/researchers. Each mentor uniquely contributes to the candidate's scientific and career growth towards independence. Dr. Nudo, the primary mentor, will help the candidate with understanding brain physiology, the cascade of cerebral cellular events that occur after stroke, grantsmanship, improving scientific writing skills for high-impact journal submissions and NIH grants, and conducting mechanistic, hypothesis driven research. Dr. Dengel, co-mentor, will be instrumental for learning how to perform FMD techniques, using Doppler ultrasound for vascular scanning and interpreting findings using electronic vessel-wall tracking software. Dr. Dawn, co-mentor, will provide lab experiences and research discussions on vascular physiology, blood flow, and autonomic control. He will facilitate a productive learning environment between the candidate and the vascular sonographers. Dr. Wood, co-mentor, will provide lab experiences and mentorship regarding vascular regulation and benchtop techniques for identifying mechanisms related to reduced blood flow, hypoxia and vascular dysfunction. Dr. Billinger will be using the ELISA techniques in Dr. Wood's lab for identifying the pro-inflammatory in plasma. Dr Rymer, co-mentor, will ensure access to the stroke patient population and resources to conduct the experiments at the hospital (St. Luke's Brain Institute). She has been part of several clinical trials and can assist the candidate with approaches and problem-solving on recruitment, consenting, and drop-outs. Research Plan: Individuals with chronic stroke demonstrate reduced blood flow in the hemiparetic limb. A better understanding of mechanistic factors that influence vascular regulation after stroke could lead to innovative rehabilitation strategies that diminish disability and improve functional outcomes. Pro-inflammatory markers are released after stroke as a result of the brain injury. The pro-inflammatory markers enter the peripheral vascular system within 24 hours post-stroke. Cytokines (TNF-a, IL-6) and vascular adhesion molecule (VCAM-1) are pro-inflammatory markers that, when present in the vascular system, can reduce production and/or release of nitric oxide, a potent vasodilator. Nitric oxide is needed for vessel dilation to occur in order to accommodate increased blood flow during periods of exercise. Although people post-stroke demonstrate altered vascular function, pilot work suggests exercise can improve blood flow in the hemiparetic limb. The candidate will recruit individuals after an acute stroke to examine the relationship between pro-inflammatory markers and vascular function (using flow-mediated dilation). Plasma samples will be analyzed to quantitatively determine the amount of pro-inflammatory markers in the plasma. Doppler ultrasound and specialized vessel wall tracking software will be used to assess vascular function. In the most innovative aspect of the project, the candidate will also explore the role of an aerobic exercise intervention during stroke rehabilitation. The candidate believes that the exercise intervention will down-regulate the effect of pro-inflammatory markers and improve vascular regulation. The candidate plans to use the results from these experiments as pilot data for a larger clinical trial. However, before a clinical trial is undertaken, it is important and essential that one understands the role of pro-inflammatory markers and vascular function during stroke recovery.