Systemic Effects of Bone Marrow-Derived MSCs on Vascular Stability

骨髓间充质干细胞对血管稳定性的系统影响

• 批准号: 8111616
• 负责人: Shibani Pati
• 金额: $ 10.59万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111616
• 关键词: Address; Adherens Junction; Animal Model; Animals; Area; Basic Science; Biological Assay; Biological Models; Biomedical Research; Blood - brain barrier anatomy; Blood Vessels; Bone Marrow; Cancer Center; Candidate Disease Gene; Cardiology; Cardiovascular Diseases; Cell Adhesion; Cell Communication; Cell Proliferation; Cell physiology; Cells; Chairperson; Childhood; Coculture Techniques; Collaborations; Cultured Cells; Data; Disease; Doctor of Philosophy; Endothelial Cells; Environment; FDA approved; Fellowship; Future; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Profile; Genes; Genomics; Goals; Health Sciences; Homing; Human; Image; In Vitro; Injury; K-18 conjugate; Knowledge; Lead; Learning; Maryland; Mediating; Medicine; Mentors; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Messenger RNA; Mission; Modality; Modeling; Mus; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ; Patients; Pediatric Surgical Procedures; Permeability; Phase I Clinical Trials; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Process; Production; Productivity; Property; Proteins; Publications; Published Comment; RNA; Regenerative Medicine; Research; Research Personnel; Resuscitation; Science; Scientist; Serum; Site; Stem Cell Research; Stem cells; System; Testing; Texas; Therapeutic; Therapeutic Effect; Tight Junctions; Time; Translating; Translations; Trauma; Traumatic Brain Injury; Universities; Vascular Endothelial Cell; Vascular Endothelium; Work; adult stem cell; angiogenesis; base; bench to bedside; career; career development; cell growth; cell type; clinical application; college; design; in vitro Assay; in vitro Model; in vivo; injured; knowledge base; meetings; migration; mouse model; professor; research and development; research study; skills; stem cell biology; stem cell therapy

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.

描述（由申请人提供）： 项目摘要 这是重新提交给 NHLBI 的为期 2 年的 K18 提案，用于干细胞研究的职业发展。主要研究者完成了她的医学博士/博士学位。她在马里兰大学获得博士学位，并选择将自己的全部精力和职业生涯奉献给生物医学研究。主要研究者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，她开始在休斯顿德克萨斯大学健康科学中心 (UTHSCH) 外科系和转化损伤研究中心 (CeTIR) 担任助理教授。 CeTIR 由创伤和复苏科学领域的先驱 John B. Holcomb 医学博士领导。 CeTIR的使命是促进伤害相关领域基础研究的转化，并将其从“实验室到临床”转化。 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中共同工作。干细胞研究和再生医学是 CeTIR 重点关注的领域。首席研究员为本次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军人物。 Edward Yeh博士是MD安德森癌症中心心脏病科主任，在成体干细胞生物学及其在心血管疾病中的应用领域做出了重大贡献。 PI 的第二位导师 Charles S. Cox 博士是 UTHSCH 的小儿外科教授，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 批准的干细胞治疗小儿创伤性脑损伤 (TBI) 一期试验的临床医生。两位导师都是各自领域的顶尖研究人员，并同意定期与 PI 会面。 在接下来的两年中，PI 将致力于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) 掌握干细胞和脉管系统体内和体外成像所需的知识和技能。在此 K18 申请中描述的 PI 项目侧重于骨髓间充质干细胞 (MSC) 和内皮细胞 (EC) 之间相互作用产生的可溶性因子的确认和表征。 PI的初步数据表明，间充质干细胞与内皮细胞接触，通过增强粘附连接和紧密连接来促进内皮稳定性，从而导致TBI后体外EC增殖、血管生成和通透性净减少，体内血脑屏障通透性降低。 PI 的总体机制假设是，间充质干细胞在与内皮细胞接触后，诱导产生一种可溶性因子，该因子可全身作用以促进血管稳定性，并且这些特性将在损伤后保留器官内皮屏障功能。在这些研究中，PI 提议使用 TBI 模型作为血管不稳定性和渗透性的体内相关性，以确定该因素的功能和存在。 在这份重新提交的 K18 计划中，候选人回应了评审员就她的候选资格、指导计划、职业发展和研究计划提出的评论。该候选人在解决有关其候选资格的问题时表现出提高的出版物效率。指导计划已经过修改，以解决审稿人对与导师相处的时间的担忧。该提案还包括针对她的职业发展目标的指导计划，即了解更多有关干细胞和脉管系统成像的知识。候选人还解决了评审员对研究计划的担忧。该提案增加了第三个目标，即尝试使用基于基因组学的方法来识别可溶性因子。 PI 还尝试修改该提案，使其更加符合审阅者的建议。 这项工作的目标是表征并最终鉴定出一种“无细胞”因子，该因子可以在体内重现干细胞的有益治疗效果，从而为患有创伤性损伤或其他病症的患者提供更可行的治疗选择由血管不稳定定义。