P2G 动员联合SDF-1β 趋化内皮祖细胞（EPC）治疗糖尿病后肢缺血的效应和机制

血管再生障碍是糖尿病缺血性血管疾病的主要发病机理。内皮祖细胞（EPC）在血管再生过程中起关键作用，但糖尿病导致外周EPC数量减少和趋化EPC向创伤部位募集的能力降低。基质细胞衍生因子（SDF-1）及其受体（CXCR4）调节EPC的趋化和迁移，拮抗CXCR4能动员EPC进入外周血，表明以CXCR4为靶点动员自体EPC是一种很有前景的治疗策略。课题组成功研发了一种新颖的CXCR4拮抗剂P2G。预研表明：P2G拮抗CXCR4能有效动员EPC、治疗正常和糖尿病小鼠后肢缺血。据此提出科学假设：P2G动员EPC进入外周血联合损伤部位SDF-1β趋化EPC进入缺血组织能有效治疗糖尿病缺血性血管疾病。本课题的主要目标是系统考察P2G动员联合SDF-1β趋化EPC治疗糖尿病缺血性血管疾病的可行性，并利用多种转基因小鼠模型解析其分子、细胞机制，为将来临床以CXCR4为靶点治疗糖尿病心血管并发症提供科学依据。

Utilization of endothelial progenitor cells (EPCs) is a promising novel therapeutic option for regeneration of diabetic ischemic tissues. But diabetes reduces EPCs in circulation and abrogates chemokine expression responsible for wound-site EPCs recruitment. Stromal cell derived factor 1 (SDF-1) and its receptor CXCR4 are extensively found to involve in mobilization of bone marrow (BM) EPCs. Antagonizing CXCR4 with a potent antagonist AMD3100 has been shown to induce EPC mobilization and stimulate ischemic angiogenesis, implying that mobilization of EPCs by targeting CXCR4 is a promising strategy for ischemic angiogenesis. ..We recently developed a novel antagonist against CXCR4, SDF-1βP2G (P2G). Our preliminary studies revealed that P2G can effectively improve ischemic angiogenesis and blood reperfusion in both diabetic and non-diabetic mice along with significant EPC mobilization. Based on these novel findings, we HYPOTHESIZE that combined use of P2G to mobilize EPCs from BM into peripheral circulation with ischemia-site administration of SDF-1β to recruit EPCs into ischemic tissue may offer a novel therapy for enhancing diabetic ischemic angiogenesis. To test this hypothesis, we will use a type 2 diabetic mouse hindlimb ischemia model to achieve the following specific aims: Aim 1: To define whether P2G mobilizes EPCs; Aim 2: To determine whether P2G mobilization and SDF-1β recruitment of EPCs enhances ischemic angiogenesis; Aim 3: To define the role of mobilized EPCs in ischemic angiogenesis. This study will verify a novel strategy to combine use of P2G’s systemic mobilization and SDF-1 wound-site recruitment of EPCs for therapy of diabetic vascular diseases.