Burn injuries represent a major public health problem, requiring medical attention for more than one million Americans annually. Despite therapeutic advances, non-healing burn wounds and excessive scarring still result in significant long-term physical and psychosocial morbidity. In this P20 Exploratory Center Grant application, we propose to perform clinical and pre-clinical research to study the role of endothelial progenitor cells (EPCs) in promoting burn wound healing. EPCs have been shown to contribute to vascularization and tissue repair in animal models of ischemia. Mobilization of EPCs into the peripheral blood has been demonstrated in burn wound patients. The proposed research will utilize: clinical resources of the Johns Hopkins Regional Burn Center, where hundreds of adults are treated each year;a mouse model of burn wound healing established by participating clinician-scientists;and expertise concerning the cellular and molecular mechanisms of angiogenesis induced by hypoxia/ischemia. The overall goal of the proposed research is to test the hypothesis that the mobilization of bone marrow-derived EPCs and their recruitment to burn wounds is a major determinant of the extent and quality of healing and that strategies designed to promote EPC mobilization and recruitment will promote burn wound healing. The proposed research is thus inherently translational. At the molecular level of analysis, we will focus on the role of hypoxia-inducible factor 1 (HIF-1), a transcription factor that functions as a master regulator of ischemiainduced angiogenesis, although its role in burn wound healing has not been investigated to date. Our highrisk strategy will involve attempting to mobilize and recruit EPCs to burn wounds by increasing the expression of HIF-1 and/or levels of cytokines encoded by HIF-1-regulated genes. To form the nucleus of the Johns Hopkins Center for Innovative Wound Healing Research, we have assembled an interactive multidisciplinary team with expertise in molecular and cellular biology, medical genetics, animal models of wound healing, and clinical burn wound care and research. This team will work together to perform a single project encompassing the innovative studies described above, which will provide the scientific foundation for clinical trials to be proposed in a subsequent P50 application, which will be submitted during year 3 of P20 funding and will lead to novel treatments to promote wound healing and prevent excessive scarring.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM078494-04
Application #
7681510
Study Section
Special Emphasis Panel (ZGM1-PPBC-9 (WH))
Program Officer
Ikeda, Richard A
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$831,241
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sarkar, Kakali; Rey, Sergio; Zhang, Xianjie et al. (2012) Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells. Cardiovasc Res 93:162-9
Prabhakar, Nanduri R; Semenza, Gregg L (2012) Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92:967-1003
Semenza, Gregg L; Prabhakar, Nanduri R (2012) The role of hypoxia-inducible factors in oxygen sensing by the carotid body. Adv Exp Med Biol 758:1-5
Zhang, Xianjie; Sarkar, Kakali; Rey, Sergio et al. (2011) Aging impairs the mobilization and homing of bone marrow-derived angiogenic cells to burn wounds. J Mol Med (Berl) 89:985-95
Xing, Dongmei; Liu, Lixin; Marti, Guy P et al. (2011) Hypoxia and hypoxia-inducible factor in the burn wound. Wound Repair Regen 19:205-13
Jiang, Xinguo; Khan, Mohammad A; Tian, Wen et al. (2011) Adenovirus-mediated HIF-1? gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. J Clin Invest 121:2336-49
Rey, Sergio; Semenza, Gregg L (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86:236-42
Zhang, Xianjie; Liu, Lixin; Wei, Xiaofei et al. (2010) Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding. Wound Repair Regen 18:193-201
Semenza, Gregg L (2010) Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol 30:648-52
Zhang, Xianjie; Wei, Xiaofei; Liu, Lixin et al. (2010) Association of increasing burn severity in mice with delayed mobilization of circulating angiogenic cells. Arch Surg 145:259-66

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