PROMISES: Progenitor Endothelial Cells as a Marker of Endothelial Injury and Repa

描述（由申请人提供）： 拟议的四年职业发展奖的长期目标是允许候选人在转化研究中发展独立的研究生涯，将危重病病理生理学的基本方面与临床结果联系起来。候选人对理解创伤、败血症或其他急性损伤患者的微循环内皮功能障碍和修复机制感兴趣。作为该奖项的一部分，她将发展侧流暗场（SDF）视频显微镜的专业知识，这是一种非侵入性技术，可直接可视化人体受试者的微循环血管和灌注。她的指导团队由许多败血症和内皮功能障碍研究领域的知名专家组成。Lyle Moldawer博士是一位杰出的调查员和有成就的导师。候选人的研究计划建立在她的导师自己的NIH资助的研究检查败血症早期先天免疫反应和适应性免疫功能障碍之间的相互作用。此外，目前的研究计划扩展了候选人以前与她的共同导师Mark S.西格尔她在多学科外科重症监护室的临床任命将提供进行跨学科转化研究的理想环境。拟议的职业发展计划包括一个多学科的计划，旨在提供密切指导，以患者为导向的临床和转化研究经验，与临床调查，统计学和流行病学的全面结构的教学课程相关联，通过在临床调查高级研究生课程招生。该研究计划的目标是描述EPCs在严重脓毒症（SS）发病前48小时内对微循环功能障碍的影响，并确定EPCs作为内皮修复标志物的潜在作用。该假说认为，脓毒症的组织缺氧，通过下调血管生成因子，为EPCs从骨髓进入循环提供了刺激，并且EPCs的动员与内皮修复和微循环灌注的恢复相关。将在SS患者的单中心、前瞻性、观察性队列研究中对这些假设进行检验，以测量SS发作前48小时内EPCs的动员和功能特性，并确定其对微循环功能障碍恢复的影响（具体目标1），将EPCs的动员与低氧诱导的血管生成因子的血浆水平相关联（具体目标2）和确定微循环功能障碍对器官恢复和住院生存的影响（具体目标3）。该奖项将培养一个专注于理解微循环内皮功能障碍和危重病修复机制的职业生涯，以开发使用祖细胞作为危重病患者疾病监测生物标志物的方法。 公共卫生相关性： 严重脓毒症是重症监护室死亡的主要原因，并对全球医疗保健系统造成巨大负担。我们的研究方法可能为严重脓毒症患者的内皮功能障碍和修复提供新的监测工具，最终改善严重脓毒症患者的护理和结局。

DESCRIPTION (provided by applicant): The long-term goal of the proposed four-year Career Development Award is to allow Candidate to develop an independent research career in translational studies linking basic aspects of critical illness pathophysiology to clinical outcomes. The candidate is interested in understanding the mechanisms of microcirculatory endothelial dysfunction and repair in patients who sustain trauma, sepsis or any other acute injury. As a part of this Award, she will develop an expertise in sidestream dark-field (SDF) video microscopy, a non-invasive technique that directly visualizes microcirculatory vessels and perfusion in human subjects. Her mentoring team features a number of renowned experts in research of sepsis and endothelial dysfunction. Her primary mentor, Dr. Lyle Moldawer, is an outstanding investigator and accomplished mentor. The candidate's research plan builds upon her mentors own NIH-funded research examining interactions between the early innate immune response and adaptive immune dysfunction in sepsis. In addition, the current research proposal expands upon the Candidate's previous research experience in studying endothelial progenitor cells (EPCs) in chronic kidney disease with her co-mentor, Dr. Mark S. Segal. Her clinical appointment in a multidisciplinary surgical intensive care unit will provide the ideal setting in which to conduct interdisciplinary translational research. The proposed career development plan incorporates a multi-disciplinary program designed to provide a closely mentored, patient-oriented clinical and translational research experience in association with a comprehensively structured didactic curriculum in clinical investigation, statistics and epidemiology through enrollment in the Advanced Postgraduate Program in Clinical Investigation. The goals of the research proposal are to characterize the effect of EPCs on microcirculatory dysfunction in the first 48 hours onset of severe sepsis (SS) and to determine the potential role of EPCs as markers of endothelial repair. The hypothesis is that tissue hypoxia in sepsis, through downregulation of angiogenic factors, provides a stimulus for the mobilization of EPCs from the bone marrow into the circulation, and that mobilization of EPCs is associated with endothelial repair and restoration of microcirculatory perfusion. These hypotheses will be tested in a single-center, prospective, observational cohort study of patients with SS in order to measure mobilization and functional properties of EPCs in the first 48 hours onset of SS and to determine their effect on the recovery of microcirculatory dysfunction (Specific Aim 1), to correlate mobilization of EPCs to the plasma levels of hypoxia-induced angiogenic factors (Specific Aim 2) and to determine the effect of microcirculatory dysfunction on organ recovery and hospital survival (Specific Aim 3). This Award will foster a career focused on understanding the mechanisms of microcirculatory endothelial dysfunction and repair in critical illness in order to develop the methodology for use of progenitor cells as biological markers for disease monitoring in critically ill patients. PUBLIC HEALTH RELEVANCE: Severe sepsis is a leading cause of mortality in the intensive care unit and imposes a large burden on healthcare systems worldwide. Our research approach may provide new monitoring tools for endothelial dysfunction and repair in patients with severe sepsis, eventually leading to improved care and outcomes for patients with severe sepsis.