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: 8059306
• 负责人: Gregg L Semenza
• 金额: $ 8.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059306
• 关键词: Adenovirus Vector; Adult; Age; Aging; American; Animal Model; Applications Grants; 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 Genetics; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Necrosis; Patients; Plasmids; Probability; Production; Public Health; Recruitment Activity; Research; Resources; Role; Scientist; Signal Transduction; Stem cells; TNFRSF5 gene; Testing; Therapeutic; Tissues; Translations; Vascularization; Work; Wound Healing; angiogenesis; cytokine; design; gene therapy; healing; high risk; hypoxia inducible factor 1; innovation; loss of function; medical attention; 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.

烧伤是一个重大的公共卫生问题，超过一百万人需要医疗护理 美国人每年。尽管治疗取得了进展，但烧伤伤口不愈合和疤痕过多仍然存在 导致显着的长期身体和心理社会发病率。在这个 P20 探索中心拨款中 应用，我们建议进行临床和临床前研究来研究内皮细胞的作用 祖细胞（EPC）促进烧伤伤口愈合。 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 EPC 调动到外设中 已在烧伤患者身上证实存在血液。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此接受治疗；一只老鼠 参与临床医生科学家建立的烧伤伤口愈合模型；以及有关的专业知识 缺氧/缺血诱导血管生成的细胞和分子机制。该项目的总体目标是 拟议的研究旨在检验以下假设：骨髓来源的 EPC 的动员及其 烧伤伤口的募集是愈合程度和质量的主要决定因素，因此策略 旨在促进 EPC 动员和募集将促进烧伤创面愈合。拟议的 因此，研究本质上是转化性的。在分子水平的分析上，我们将重点关注 缺氧诱导因子 1 (HIF-1)，一种转录因子，作为缺血诱导的主要调节因子 血管生成，尽管迄今为止尚未研究其在烧伤伤口愈合中的作用。我们的高风险 该战略将涉及尝试动员和招募 EPC 来烧伤伤口，方法是增加 HIF-1 的表达和/或 HIF-1 调节基因编码的细胞因子的水平。为了形成核心 约翰·霍普金斯创新伤口愈合研究中心，我们组建了一个交互式多学科 拥有分子和细胞生物学、医学遗传学、伤口动物模型专业知识的团队 愈合、临床烧伤伤口护理和研究。该团队将共同完成一个项目 涵盖上述创新研究，将为临床提供科学基础 将在后续 P50 申请中提议进行试验，该申请将在 P20 资助的第 3 年期间提交 并将带来促进伤口愈合和防止过度疤痕的新疗法。

项目成果

Hypoxia and hypoxia-inducible factor in the burn wound.

烧伤伤口中缺氧和缺氧诱导因子。

• DOI: 10.1111/j.1524-475x.2010.00656.x
• 发表时间: 2011-03
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Xing D;Liu L;Marti GP;Zhang X;Reinblatt M;Milner SM;Harmon JW
• 通讯作者: Harmon JW

Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding.

• DOI: 10.1111/j.1524-475x.2010.00570.x
• 发表时间: 2010-03
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Zhang X;Liu L;Wei X;Tan YS;Tong L;Chang R;Ghanamah MS;Reinblatt M;Marti GP;Harmon JW;Semenza GL
• 通讯作者: Semenza GL

Aging impairs the mobilization and homing of bone marrow-derived angiogenic cells to burn wounds.

衰老会损害骨髓来源的血管生成细胞对烧伤伤口的动员和归巢。

• DOI: 10.1007/s00109-011-0754-2
• 发表时间: 2011
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: Zhang,Xianjie;Sarkar,Kakali;Rey,Sergio;Sebastian,Raul;Andrikopoulou,Efstathia;Marti,GuyP;Fox-Talbot,Karen;Semenza,GreggL;Harmon,JohnW
• 通讯作者: Harmon,JohnW

Association of increasing burn severity in mice with delayed mobilization of circulating angiogenic cells.

小鼠烧伤严重程度增加与循环血管生成细胞动员延迟的关联。

• DOI: 10.1001/archsurg.2009.285
• 发表时间: 2010
• 期刊: Archives of surgery (Chicago, Ill. : 1960)
• 作者: Zhang,Xianjie;Wei,Xiaofei;Liu,Lixin;Marti,GuyP;Ghanamah,MohammedS;Arshad,MuhammadJ;Strom,Lori;Spence,Robert;Jeng,James;Milner,Stephen;Harmon,JohnW;Semenza,GreggL
• 通讯作者: Semenza,GreggL