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）：项目摘要这是一个为期2年的K18提案重新提交给NHLBI在干细胞研究的职业发展。主要研究者完成了MD。/ PhD.在马里兰州大学，并选择了奉献她的全部努力和职业生涯的生物医学研究。首席研究员最近完成了她在德克萨斯大学休斯顿分校和贝勒医学院的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）外科系和转化损伤研究中心（CeTIR）的助理教授。CeTIR由John B博士领导。霍尔科姆医学博士，创伤和复苏科学领域的先驱。CeTIR的使命是促进损伤相关领域基础研究的转化，并将其从“实验室到临床”。CeTIR由一群基础科学家和临床医生组成，他们在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关注的具体领域。主要研究者为K18项目选择了两位导师，他们都是干细胞生物学及其临床应用领域的领导者。Edward Yeh博士是MD安德森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。Dr. Charles S. PI的第二位导师考克斯是UTHSCH的小儿外科教授，是将干细胞治疗转化为患者的领导者。他是第一位领导FDA批准的在儿科创伤性脑损伤（TBI）中使用干细胞的1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，他们同意定期与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）通过扩大和加强她在干细胞和创伤相关研究方面的知识基础，2）通过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项目重点关注骨髓间充质干细胞（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，与内皮细胞接触的MSC通过增强粘附连接和紧密连接来促进内皮稳定性，这导致体外EC增殖、血管生成和渗透性的净减少以及TBI后体内血脑屏障渗透性的降低。PI的总体机制假设是MSC在与EC接触后诱导产生可溶性因子，其全身性地起作用以促进血管稳定性，并且这些品质将在损伤后保持器官-内皮屏障功能。在这些研究中，PI建议使用TBI模型作为血管不稳定性和渗透性的体内相关性，以确定因子的功能和存在。 在这份重新提交的K18计划中，候选人阐述了审查人员就其候选人资格、指导计划、职业发展和研究计划提出的意见。候选人在解决与其候选资格有关的问题的出版物中表现出更高的生产力。对指导计划进行了修改，以解决审查人员对与指导人员相处时间的关切。该提案还包括一个指导计划，她的职业发展目标是学习更多关于干细胞和血管成像。候选人还解决了审查者对研究计划的担忧。第三个目标已被添加到这个建议，试图确定可溶性因子使用基因组学为基础的方法。PI还试图修改提案，以便按照审查人员的建议更加突出重点。 这项工作的目标是表征并最终确定一种“无细胞”因子，该因子可以概括干细胞在体内的有益治疗效果，从而为患有创伤性损伤或由血管不稳定定义的其他病症的患者提供更可行的治疗选择。