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.
This proposal describes a therapeutic effect of human bone marrow derived mesenchymal stem cells (MSCs) on blood vessel stability. The ultimate goal of this project is to produce a cell free treatment option derived from stem cells for the treatment of injured patients.
|Gibb, Stuart L; Zhao, Yuhai; Potter, Daniel et al. (2015) TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury. Stem Cells 33:3530-44|
|Menge, Tyler; Gerber, Michael; Wataha, Kathryn et al. (2013) Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-Cadherin/Î²-catenin signaling pathway. Stem Cells Dev 22:148-57|
|Menge, Tyler; Zhao, Yuhai; Zhao, Jing et al. (2012) Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury. Sci Transl Med 4:161ra150|