HIF-1-Regulated Endothelial Progenitor Cell Recruitment in Burn Wound Healing

描述(由申请者提供)：烧伤是一个主要的公共卫生问题，每年需要100多万美国人接受医疗护理。尽管治疗取得了进展，但无法愈合的烧伤创面和过度的疤痕仍会导致严重的长期生理和心理疾病。在P20探索中心赠款申请中，我们建议进行临床和临床前研究，以研究内皮祖细胞(EPC)在促进烧伤创面愈合中的作用。在动物的缺血模型中，内皮祖细胞已被证明有助于血管形成和组织修复。烧伤创面患者外周血中内皮祖细胞的动员已得到证实。这项拟议的研究将利用：约翰·霍普金斯地区烧伤中心的临床资源，每年有数百名成年人在该中心接受治疗；参与研究的临床医生和科学家建立的烧伤创面愈合小鼠模型；以及关于缺氧/缺血诱导血管生成的细胞和分子机制的专业知识。这项拟议研究的总体目标是验证这样一种假设，即骨髓来源的EPC的动员和它们对烧伤创面的募集是愈合程度和质量的主要决定因素，而那些旨在促进EPC动员和募集的策略将促进烧伤创面的愈合。因此，拟议的研究具有内在的翻译性。在分子水平上，我们将重点讨论缺氧诱导因子1(HIF-1)的作用，HIF-1是一种转录因子，在缺血诱导的血管生成中起主要调节作用，尽管迄今为止还没有研究它在烧伤创面愈合中的作用。我们的高风险策略将包括通过增加HIF-1的表达和/或由HIF-1调节的基因编码的细胞因子水平来动员和招募内皮祖细胞到烧伤创面。为了形成约翰·霍普金斯创新型伤口愈合研究中心的核心，我们组建了一个互动式的多学科团队，拥有创伤愈合的分子和细胞生物学、医学遗传学和动物模型以及临床烧伤伤口护理和研究方面的专业知识。该团队将共同努力执行一个包含上述创新研究的单一项目，这将为随后的P50申请中提出的临床试验提供科学基础，该申请将在P20资助的第三年提交，并将导致促进伤口愈合和防止过度疤痕的新疗法。

DESCRIPTION (provided by applicant): 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 those 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 high-risk 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, and 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.