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

HIF-1 调节的内皮祖细胞募集在烧伤创面愈合中的作用

• 批准号: 7139405
• 负责人: Gregg L Semenza
• 金额: $ 80.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139405
• 关键词: angiogenesis; blood proteins; burns; cell cell interaction; clinical research; cytokine; disease /disorder model; erythropoietin; flow cytometry; histology; human subject; hypoxia inducible factor 1; imaging /visualization /scanning; injury; laboratory mouse; nonblood rheology; patient oriented research; scars; tissue /cell culture; wound healing

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.

描述（由申请人提供）：烧伤是一个主要的公共卫生问题，每年需要超过一百万美国人的医疗照顾。 尽管治疗取得了进展，但不愈合的烧伤伤口和过度疤痕仍然导致严重的长期身体和心理疾病。 在这项P20探索中心资助申请中，我们建议进行临床和临床前研究，以研究内皮祖细胞（EPCs）在促进烧伤创面愈合中的作用。 在缺血动物模型中，内皮祖细胞已被证明有助于血管形成和组织修复。 在烧伤患者中已经证实了EPCs进入外周血的动员。 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接受治疗;参与临床医生-科学家建立的烧伤伤口愈合小鼠模型;以及有关缺氧/缺血诱导血管生成的细胞和分子机制的专业知识。 拟议研究的总体目标是检验这一假设，即骨髓来源的EPCs的动员及其向烧伤创面的募集是愈合程度和质量的主要决定因素，旨在促进EPC动员和募集的那些策略将促进烧伤创面愈合。 因此，拟议的研究本质上是翻译的。 在分子水平上的分析，我们将集中在缺氧诱导因子1（HIF-1）的作用，转录因子，作为一个主调节缺血诱导的血管生成的功能，虽然它在烧伤创面愈合的作用还没有被调查的日期。 我们的高风险策略将涉及通过增加HIF-1的表达和/或HIF-1调节基因编码的细胞因子水平来动员和招募EPCs来烧伤创面。 为了形成约翰霍普金斯创新伤口愈合研究中心的核心，我们组建了一个互动的多学科团队，拥有分子和细胞生物学，医学遗传学，伤口愈合的动物模型以及临床烧伤伤口护理和研究方面的专业知识。 该团队将共同开展一个包含上述创新研究的单一项目，该项目将为后续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3年提交，并将导致新的治疗方法，以促进伤口愈合并防止过度疤痕。