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

烧伤是一个重大的公共卫生问题，需要100多万人进行医疗护理。 每年都有美国人参加。尽管治疗取得了进展，但无法愈合的烧伤伤口和过度的疤痕仍然存在 导致严重的长期生理和心理社会疾病。在这份P20探索中心奖助金 应用，我们建议进行临床和临床前研究，以研究内皮细胞的作用 祖细胞在促进烧伤创面愈合中的作用。EPC已被证明有助于 缺血动物模型中的血管形成和组织修复。将内皮祖细胞动员到外周 在烧伤创面的患者中已经发现了血液。拟议的研究将利用：临床资源 约翰·霍普金斯地区烧伤中心，每年有数百名成年人在那里接受治疗；一只老鼠 参与的临床医生和科学家建立的烧伤创面愈合模型；以及关于 缺氧/缺血诱导血管生成的细胞和分子机制。该计划的总体目标 拟议的研究是为了验证这样一种假设，即骨髓来源的内皮祖细胞及其 烧伤创面的愈合是愈合程度和质量的主要决定因素，也是战略 旨在促进EPC动员和招募将促进烧伤创面愈合。建议数 因此，研究本质上是翻译的。在分子水平的分析上，我们将重点放在 缺氧诱导因子-1(HIF-1)是一种转录因子，在脑缺血诱导中发挥主要调节作用 血管生成，尽管它在烧伤创面愈合中的作用到目前为止还没有研究。我们的高风险 战略将包括试图动员和招募EPC通过增加 HIF-1的表达和/或由HIF-1调控的基因编码的细胞因子水平。以形成世界的核心 约翰霍普金斯创新伤口愈合研究中心，我们集合了一个互动的多学科 在分子和细胞生物学、医学遗传学、创伤动物模型方面拥有专业知识的团队 治疗和临床烧伤创面护理和研究。这个团队将共同完成一个单独的项目 包括上述创新性研究，将为临床提供科学基础 试验将在随后的P50申请中提出，该申请将在P20供资的第三年提交 并将导致新的治疗方法，以促进伤口愈合和防止过度疤痕。

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.