This 2-year Career Enhancement Award is focused on providing the physician-scientist candidate with new tools and opportunities to accomplish the directed differentiation and optimization of human stem cell populations for use in microvascular restitution. Vascular infrastructure is an essential ingredient for recovery from devastating lung injury, and is integral to the success of tissue engineering efforts. One major challenge to the successful execution of an engineered microvascular network is the lack of a readily usable endothelial cell population. This is an essential ingredient if immunosuppression and graft versus host issues are to be avoided in the already critically ill patients that may receive these engineered networks as a rescue therapy. The two specific aims will focus on the manipulation of signaling pathways and cell cycle control methods in CD14+ peripheral blood mononuclear cells (Aim One) and CD34+ bone marrow stem-progenitor cells (Aim Two) in order to speed directed differentiation to an endothelial phenotype that is optimized for vasculogenesis. This will be accomplished through the use of lentiviral gene transduction. The viability and efficacy of these cells in 3-D matrices derived from human fibroblasts, and in transplantation models in immunodeficient NOD-scid IL2Rg-/- (NOG) mice will be tested. The directed differentiation of human embryonic stem cells to a microvascular endothelial phenotype will also be pursued. These investigations will lay the groundwork for future studies on stem cell populations in tissue-engineered microvascular networks to facilitate new parenchyma! growth following catastrophic pulmonary illness. The sponsor's lab in the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University provides an outstanding training environment for translational stem cell biology. The sponsor's decade of experience as a leader in stem cell research, a first rate team of senior investigators, state-of-the-art equipment, and a mouse transplantation core facility are all made possible by intense and far-sighted institutional commitment to this field of inquiry. PUBLIC HEALTH IMPACT: Life-threatening injury to the lung can destroy normal tissues. The capacity to recuperate depends upon networks of tiny nutrient blood vessels that allow new lung to grow. This Career Enhancement Award will provide special training in stem cells to a physician caring for children with lung injury in the intensive care unit. Using techniques learned in a world-class stem cell center, it may be possible to encourage the development of new blood vessels and increase the pace and success of lung recovery from severe illness. ? ? ?
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