Systemic Effects of Bone Marrow-Derived MSCs on Vascular Stability

描述(由申请者提供)：项目摘要这是一份为期两年的K18计划，重新提交给NHLBI，用于干细胞研究的职业发展。首席调查员完成了她的医学博士学位。在马里兰大学，她选择将自己的全部努力和职业生涯献给生物医学研究。这位首席研究员最近在德克萨斯大学休斯顿分校和贝勒医学院完成了她在创伤性脑损伤研究方面的博士后研究。2008年11月，她开始担任德克萨斯大学休斯顿健康科学中心(UTHSCH)外科和转化性损伤研究中心(CETIR)的助理教授。CeTIR由创伤和复苏科学领域的先驱约翰·B·霍尔科姆博士领导。CeTIR的使命是促进与伤害相关领域的基础研究的翻译，并将其从“长凳到床边”翻译。CeTIR由一群基础科学家和临床医生组成，他们在促进协作和翻译的理想环境和环境中共同工作。干细胞研究和再生医学是CeTIR的具体重点领域。首席研究人员为这项K18计划选择了两名导师，他们都是干细胞生物学及其临床应用领域的领导者。Edward Yeh博士是MD Anderson癌症中心心脏病科主任，在成人干细胞生物学和心血管疾病应用领域做出了重大贡献。查尔斯·S·考克斯博士是该协会的第二位导师，是加州大学附属卫生研究院的儿科外科学教授，也是干细胞疗法向患者转化的领军人物。他是第一位领导FDA批准的使用干细胞治疗儿童创伤性脑损伤(TBI)的1期试验的临床医生。这两位导师都是各自领域的顶级研究人员，已同意定期与PI会面。 在接下来的两年里，PI的目标是通过以下方式发展她的职业生涯：1)拓宽和加强她在干细胞和创伤相关研究方面的知识基础；2)接受导师和同事的科学指导和指导；3)掌握干细胞和血管系统体内和体外成像所需的知识和技能。本K18申请中描述的PI项目专注于骨髓间充质干细胞(MSCs)和内皮细胞(ECs)之间相互作用产生的可溶性因子(S)的确认和表征。PI的初步数据表明，MSCs与内皮细胞接触后，通过加强黏附连接和紧密连接促进内皮稳定性，从而导致体外内皮细胞增殖、血管生成和通透性的净减少，并降低了脑损伤后体内的血脑屏障通透性。PI的总体机制假说是，MSCs与内皮细胞接触后，诱导产生一种可溶性因子(S)，该因子具有促进血管稳定性的系统作用，这些特性将保护损伤后的器官-内皮屏障功能。在这些研究中，PI建议使用脑外伤模型作为体内血管不稳定性和通透性的相关性，以确定该因子的功能和存在(S)。 在这份重新提交的K18计划中，候选人回答了评审员对她的候选人资格、指导计划、职业发展和研究计划提出的意见。这位候选人在回答有关她的候选人资格的问题时，在出版物上表现出了更高的生产力。指导计划已被修改，以解决审查员对与导师相处的时间的担忧。这项提议还包括一项指导计划，以实现她的职业发展目标，即学习更多关于干细胞成像和血管系统的知识。候选人还回答了评审员对研究计划的关注。这项提议增加了第三个目标，即试图使用基于基因组学的方法来识别可溶性因素。国际和平研究所还试图修改该提案，以便按照审查员的建议使其更加突出重点。 这项工作的目标是表征并最终确定一种能够概括体内干细胞有益治疗效果的“无细胞”因子(S)，从而为创伤或其他由血管不稳定定义的疾病患者提供更可行的治疗选择。

DESCRIPTION (provided by applicant): Project Summary This is a 2-year K18 proposal re-submitted to NHLBI for career development in stem cell research. The principal investigator completed her MD./PhD. at the University of Maryland and has chosen to dedicate her full effort and career to biomedical research. The principal investigator has recently completed her post-doctoral fellowship in traumatic brain injury research at the University of Texas-Houston and Baylor College of Medicine. In November 2008, she started a position as Assistant Professor in the Department of Surgery and the Center for Translational Injury Research (CeTIR) at the University of Texas Health Science Center at Houston (UTHSCH). CeTIR is led by Dr. John B. Holcomb MD, a pioneer in the field of trauma and resuscitation science. CeTIR's mission is to promote the translation of basic research in areas relevant to injury and translate them from "bench to bedside". CeTIR is composed of a group of basic scientists and clinicians who work together in an ideal setting and environment that promotes collaboration and translation. Stem cell research and regenerative medicine are specific areas of focus for CeTIR. The principal investigator has chosen two mentors for this K18 proposal who are both leaders in the field of stem cell biology and its clinical application. Dr. Edward Yeh is Chairman of the Department of Cardiology at MD Anderson Cancer Center and has made significant contributions in the field of adult stem cell biology and application to cardiovascular disease. Dr. Charles S. Cox, the PI's second mentor, is a professor of pediatric surgery at UTHSCH and is a leader in the translation of stem cell therapy to patients. He is the first clinician to lead an FDA approved phase 1 trial for the use of stem cells in pediatric traumatic brain injury (TBI). Both mentors are top-tier researchers in their respective fields have agreed to meet with the PI on a regular basis. Over the next two years the PI will aim to develop her career by: 1) by broadening and strengthening her knowledge base in stem cells and trauma-related research, 2) by receiving scientific guidance and direction from mentors and colleagues and 3) mastering the knowledge and skills necessary for in vivo and in vitro imaging of stem cells and vasculature. The PI's project described in this K18 application focuses on the confirmation and characterization of soluble factor(s) produced by interactions between bone-marrow derived mesenchymal stem cells (MSCs) and endothelial cells (ECs). The PI's preliminary data suggests that MSCs in contact with endothelial cells promote endothelial stability by enhancing adherens junctions and tight junctions, which results in a net decrease in EC proliferation, angiogenesis and permeability in vitro and decreased blood-brain-barrier permeability in vivo after TBI. The PI's overall mechanistic hypothesis is that MSCs, following contact with ECs, induce production of a soluble factor(s) that acts systemically to promote vascular stability, and these qualities will preserve organ-endothelial barrier function after injury. In these studies, the PI proposes to use a model of TBI as an in vivo correlate of vascular instability and permeability to determine the function and existence of the factor(s). In this resubmitted K18 plan the candidate addresses comments posed by the reviewers concerning her candidacy, mentoring plan, career development and research plan. The candidate demonstrates increased productivity in publications to address questions concerning her candidacy. The mentoring plan has been modified to address concerns from reviewers pertaining to time spent with mentors. This proposal also includes a mentoring plan for her career development goal of learning more about imaging of stem cells and vasculature. The candidate also addresses concerns from the reviewer pertaining to the research plan. A third aim has been added to this proposal that attempts to identify soluble factors using a genomics based approach. The PI has also attempted to modify the proposal so that it is more focused as recommended by the reviewers. The goal of this work is to characterize and to ultimately identify a "cell free" factor(s) that can recapitulate the beneficial therapeutic effects of stem cells in vivo, thus resulting in a more feasible therapeutic option for patients with traumatic injury or other conditions defined by vascular instability.