Systemic Effects of Bone Marrow-Derived MSCs on Vascular Stability

这是一份为期两年的K18提案，重新提交给NHLBI，用于干细胞研究的职业发展。首席研究员完成了她的医学博士/博士学位。并选择将她的全部精力和职业生涯奉献给生物医学研究。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创伤性脑损伤研究的博士后研究。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）外科和转化损伤研究中心（CeTIR）的助理教授。CeTIR由John B. Holcomb博士领导，他是创伤和复苏科学领域的先驱。CeTIR的使命是促进与损伤相关领域的基础研究的转化，并将其从“实验室”转化为“临床”。CeTIR由一群基础科学家和临床医生组成，他们在一个促进合作和翻译的理想环境中共同工作。干细胞研究和再生医学是CeTIR特别关注的领域。首席研究员为这项K18提案选择了两位导师，他们都是干细胞生物学及其临床应用领域的领导者。叶博士是MD安德森癌症中心心脏病学主任，在成体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（Charles S. Cox）博士是该项目的第二位导师，他是UTHSCH的儿科外科教授，也是将干细胞疗法转化为患者的领导者。他是第一位领导FDA批准的在儿童创伤性脑损伤（TBI）中使用干细胞的一期试验的临床医生。两位导师都是各自领域的顶级研究人员，并同意定期与PI会面。

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.