Examining Vascular Regulation Following Acute Stroke

描述（由申请人提供）：该指导职业发展奖的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接触、经验和可信度； 2）获得对于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； 3) 执行综合培训计划并将其扩展为独立研究职业，并提交 R01 申请。支持其长期目标的候选人的近期目标将集中于：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导致的机械性血管变化； 2) 获得进行血流介导扩张（FMD）、多普勒超声和专业血管壁跟踪软件实验和数据分析的基本技能； 3）了解中风康复早期有氧运动如何减少血管功能障碍； 4) 收集结果和试点数据，成为 R01 提交的独立调查员。 候选人将获得的指导、培训计划和环境都是强有力的，将确保成功的职业发展。该职业发展奖的导师拥有与候选人互补的背景和经验，他们致力于帮助她取得成功并实现她的目标。 Billinger 博士的导师拥有 NIH 资助的经验和记录、大量出版物以及指导初级教师/研究人员的历史。每位导师都为候选人的科学和职业发展、走向独立做出了独特的贡献。 主要导师 Nudo 博士将帮助候选人了解大脑生理学、中风后发生的一系列脑细胞事件、资助、提高高影响力期刊提交和 NIH 资助的科学写作技能，以及进行机械的、假设驱动的研究。 联合导师 Dengel 博士将有助于学习如何执行 FMD 技术、使用多普勒超声进行血管扫描以及使用电子血管壁跟踪软件解释结果。 共同导师 Dawn 博士将提供有关血管生理学、血流和自主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检查人员之间富有成效的学习环境。 联合导师伍德博士将提供有关血管调节和台式技术的实验室经验和指导，以识别与血流量减少、缺氧和血管功能障碍相关的机制。 Billinger 博士将在 Wood 博士的实验室中使用 ELISA 技术来识别血浆中的促炎物质。 联合导师 Rymer 博士将确保获得中风患者群体和资源，以便在医院（圣卢克大脑研究所）进行实验。她参与了多项临床试验，可以协助候选人解决​​招募、同意和退出方面的问题。 研究计划：慢性中风患者的偏瘫肢体血流量减少。更好地了解影响中风后血管调节的机制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。中风后，由于脑损伤，促炎标记物会释放。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）和血管粘附分子（VCAM-1）是促炎标记物，当存在于血管系统中时，可以减少一氧化氮（一种有效的血管扩张剂）的产生和/或释放。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。尽管中风后的人表现出血管功能的改变，但试点工作表明运动可以改善偏瘫肢体的血流量。候选人将招募急性中风后的个体来检查促炎标记物和血管功能之间的关系（使用血流介导的扩张）。将分析血浆样本以定量测定血浆中促炎标记物的量。多普勒超声和专门的血管壁跟踪软件将用于评估血管功能。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过程中的作用。该候选人认为，运动干预将下调促炎标志物的作用并改善血管调节。候选人计划使用这些实验的结果作为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中风恢复过程中的作用是重要且必要的。

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.