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: 7679318
• 负责人: Gregg L Semenza
• 金额: $ 8.19万
• 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/7679318
• 关键词: Adenovirus Vector; Adult; Age; Aging; American; Animal Model; Applications Grants; Attention; Basic Science; Bone Marrow; Brain Hypoxia-Ischemia; Burn Centers; Burn injury; Caring; Cell Nucleus; Child; Cicatrix; Clinical; Clinical Trials; Cytokine Gene; Cytokine Signaling; Foundations; Funding; Genes; Genetic; Genetic Models; Goals; Healed; Homing; Impaired wound healing; Ischemia; Lead; Medical; Medical Genetics; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Necrosis; Numbers; Patients; Plasmids; Probability; Production; Public Health; Recruitment Activity; Research; Resources; Risk; Role; Scientist; Signal Transduction; Stem cells; TNFRSF5 gene; Testing; Therapeutic; Tissues; Translations; Vascularization; Work; Wound Healing; angiogenesis; cytokine; design; gene therapy; healing; hypoxia inducible factor 1; innovation; loss of function; mouse model; multidisciplinary; novel; peripheral blood; pre-clinical research; prevent; psychosocial; recombinant human erythropoietin; response; transcription factor; wound; wound vascularization

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.

烧伤是一个主要的公共卫生问题，需要医疗照顾的人数超过100万。 美国人每年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存在， 导致严重的长期身体和心理疾病。P20探索中心 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（EPCs）促进烧伤创面愈合。EPCs已被证明有助于 血管化和组织修复在缺血动物模型中的作用。动员EPC进入外周 在烧伤患者中已经证实了血液。拟议的研究将利用：临床资源 在约翰霍普金斯地区烧伤中心，每年有数百名成年人接受治疗;一只老鼠 参与的临床医生-科学家建立的烧伤伤口愈合模型; 缺氧/缺血诱导血管生成的细胞和分子机制。的总体目标 拟议的研究是为了验证骨髓来源的EPCs及其动员的假设， 招募烧伤创面是愈合的程度和质量的主要决定因素， 旨在促进EPC动员和募集将促进烧伤创面愈合。拟议 因此，研究本质上是翻译性的。在分子水平的分析中，我们将重点关注 缺氧诱导因子1（HIF-1）是一种转录因子，作为缺血诱导的脑缺血的主要调节因子， 血管生成，尽管其在烧伤伤口愈合中的作用至今尚未被研究。我们的高风险 战略将涉及试图动员和招募EPC烧伤伤口，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的水平。形成了 约翰霍普金斯创新伤口愈合研究中心，我们已经组装了一个互动的多学科 具有分子和细胞生物学、医学遗传学、创伤动物模型等专业知识的团队 愈合和临床烧伤伤口护理和研究。这个团队将共同完成一个项目 包括上述创新研究，这将为临床研究提供科学基础。 在随后的P50申请中提出的试验，将在P20资助的第3年提交 并将导致促进伤口愈合和防止过度结疤的新治疗。