Recruiting activated endothellal progenitor cells to wounds by hyperoxia & SDF-1a

通过高氧将活化的内皮祖细胞募集到伤口

• 批准号: 7450621
• 负责人: Omaida C Velazquez
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450621
• 关键词: Accounting; Acute; Adverse effects; Affect; American; Applications Grants; Beds; Blood; Blood Circulation; Bone Marrow; Bone Marrow Cells; CXCR4 Receptors; Cells; Chronic; Clinical; Complications of Diabetes Mellitus; Count; Cutaneous; Daily; Defect; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Disease; Dose; Foundations; Gelatinase B; Genetic; Goals; Growth; Growth Factor; Healed; Hematopoietic Stem Cell Mobilization; Hindlimb; Homing; Hyperbaric Oxygen; Hyperoxia; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Intervention; Ischemia; Leg; Ligands; Lower Extremity; Marrow; Mediating; Modeling; Mus; Nitric Oxide; Numbers; Patients; Peripheral; Peripheral arterial disease; Plasma; Play; Proto-Oncogene Protein c-kit; Protocols documentation; Recruitment Activity; Refractory; Reporting; Research Proposals; Role; Signal Pathway; Signal Transduction; Stem Cell Factor; Stem cells; Streptozocin; Stromal Cells; Testing; Therapeutic; United States Food and Drug Administration; Work; Wound Healing; chemokine; clinically relevant; cytokine; diabetic; diabetic wound healing; erucylphosphocholine; healing; in vivo; non-diabetic; novel; planetary Atmosphere; progenitor; receptor; response; stem; vasculogenesis; wound

DESCRIPTION (provided by applicant): It has been estimated that up to 2 million Americans suffer from non-healing lower extremity wounds, most as a complication of Diabetes. Bone marrow-derived endothelial progenitor cells (BMD EPC) contribute to wound healing since these progenitor/stem cells are the key cellular effectors of post-natal vasculogenesis. BMD EPC are deficient in Diabetes. Hyperoxia induced by hyperbaric oxygen (HBO2) treatments is used as a safe, FDA- approved, adjunctive therapy to stimulate wound healing in diabetic patients, but the mechanisms of action are poorly understood and HBO2 is not uniformly effective, particularly in diabetic patients with associated peripheral arterial disease (PAD), accounting for the fact that diabetic/ischemic chronic non-healing lower extremity wounds continue to be an unsolved clinical problem. In preliminary studies, we have determined that hyperoxia, induced by a clinically relevant HBO2 protocol, increases nitric oxide (.NO) levels within femoral bone marrow, accelerates the spontaneous revascularization of surgically induced hindlimb ischemia, and increases the number of BMD EPC in circulation. Additional preliminary studies indicate that Stromal cell- derived growth factor 11 (SDF-1), a chemokine that mediates EPC homing via its receptor CXCR4, is decreased in diabetic wounds and SDF-1 wound-injections partially restores the diabetic defect in wound BMD EPC recruitment, and (together with hyperoxia) synergistically enhances diabetic wound healing. Our overall goal is to develop new strategies for treating patients with chronic wounds of the legs. We hypothesized that hyperoxia induces release of BMD EPC and that these cells may then be recruited into wounds in increased numbers by virtue of their hyperoxia-induced activation and their increased numbers within the blood pool; however, local wound interventions that enhance EPC homing (such as increasing level of EPC homing chemochine, SDF-1) may be crucial for optimal therapeutic recruitment of these progenitor cells to wounds complicated by diabetes and ischemia. We further hypothesized that the delineation of the mechanisms that result in hyperoxia-induced progenitor/stem cell release will serve as the foundation for identifying novel and potentially synergistic targets for further enhancing therapeutic BMD EPC release and their recruitment into non-healing wounds. The specific goals of this research proposal are: 1.To determine the efficacy of hyperoxia (alone and in combination with SDF-1 local wound treatment) for inducing therapeutic EPC release and recruitment into diabetic/ischemic wounds, and determine if that plasma SDF-1 levels are predictive of EPC counts and wound healing in diabetic patients with PAD and in genetic murine models of diabetes. 2. To elucidate the mechanism of progenitor/stem cell mobilization by hyperoxia.In this grant application entitled Recruiting Activated Endothelial Progenitor Cells to Wounds by Hyperoxia & SDF-11 , we propose to study three fundamental questions that if answered may revolutionize the field of wound healing: (1) Is the systemic level of SDF-11 a key predictor of wound healing in diabetic patients with PAD? (2) Can targeted optimal hyperoxia exposures and wound chemokine manipulations heal wounds affected by both diabetes and ischemia? And (3) what are the downstream mechanisms of hyperoxia-induced stem cell mobilization?

描述（由申请人提供）：据估计，多达200万美国人患有不愈合的下肢伤口，最多是糖尿病的并发症。骨髓来源的内皮祖细胞（BMD EPC）有助于伤口愈合，因为这些祖细胞/干细胞是产后血管发生的关键细胞效应。 BMD EPC缺乏糖尿病。由高压氧（HBO2）诱导的高氧用作安全，FDA批准的，辅助治疗，以刺激糖尿病患者的伤口愈合，但作用机制却很难理解，HBO2却不统一，尤其是在糖尿病患者的糖尿病患者中均与较低的糖尿病患者有关，以降低糖尿病患者的疾病，以造成糖尿病性的疾病（降低/疾病），以疾病的疾病（PAD）发生疾病（PAID），而不是疾病（PAID），并且是疾病的事实（PAID）。是一个未解决的临床问题。在初步研究中，我们确定由临床相关的HBO2方案诱导的高氧增加了股骨骨髓内一氧化氮（.NO）水平，可加速手术诱导的HINDLIMB缺血的自发性血运重建，并增加循环中BMD EPC的数量。 Additional preliminary studies indicate that Stromal cell- derived growth factor 11 (SDF-1), a chemokine that mediates EPC homing via its receptor CXCR4, is decreased in diabetic wounds and SDF-1 wound-injections partially restores the diabetic defect in wound BMD EPC recruitment, and (together with hyperoxia) synergistically enhances diabetic wound healing.我们的总体目标是制定新策略，以治疗腿部慢性伤口的患者。我们假设高氧诱导BMD EPC的释放，然后可以将这些细胞招募到伤口中，以增加数量，这是由于其高氧诱导的激活及其在血库中的增加而增加。然而，局部伤口干预措施增强了EPC寄养（例如EPC归巢化学胆碱水平，SDF-1）对于最佳治疗性募集这些祖细胞对糖尿病和缺血复杂的伤口至关重要。我们进一步假设，导致高氧诱导的祖细胞/干细胞释放的机制的描述将是识别新型且潜在的协同靶标，以进一步增强治疗性BMD EPC及其招募，并将其招募到非骨骼伤口中。该研究提案的具体目标是：1。确定高氧（单独并与SDF-1结合局部伤口治疗）诱导治疗性EPC释放并招募糖尿病/缺血性伤口的功效，并确定血浆SDF-1水平是否可以预测EPC计数和糖尿病患者的糖尿病患者的EPC计数和伤口愈合。 2。为了通过高氧阐明祖细胞/干细胞动员的机制。在此授予申请中，标题为“招募活化活化的内皮内皮祖细胞”通过高氧和SDF-11的伤口，我们建议研究三个基本问题，如果答复的话，如果回答的话，可以彻底改变SDF-11的系统性疾病。 （2）靶向最佳的高氧暴露和伤口趋化因子操纵可以治愈受糖尿病和缺血影响的伤口吗？ （3）高氧诱导的干细胞动员的下游机制是什么？