Endothelial Progenitor Cell Recruitment in Diabetic Mice

描述（由申请人提供）：糖尿病患者在伤口愈合和对缺血性应激反应的能力方面存在缺陷。对这种受损的血管再生能力的机制知之甚少。最近，内皮前体细胞（EPCs）已被公认为被招募到新血管形成的网站。我们实验室的初步工作表明，与正常对照小鼠相比，糖尿病小鼠（db/db，NOD和链脲佐菌素诱导）在动员和招募内皮前体细胞（EPCs）到伤口或缺血肢体的能力方面存在特异性缺陷。正常小鼠中EPC募集的重要作用损害伤口愈合和对急性缺血的反应。糖尿病小鼠中的这种功能障碍性再生新血管形成可以通过腺病毒介导的血管生成生长因子（如血管生成素-1（Angiopoietin-1，Ang-1））的过表达来纠正，所述血管生成生长因子募集可以纠正糖尿病伤口愈合障碍和对缺血的不良反应的EPC。我们研究的总体目标是了解EPCs在伤口愈合和缺血反应中动员和招募到靶组织的机制，并了解这些机制如何受到糖尿病的损害。我们的工作假设是，招募骨髓来源的EPCs是必不可少的，在伤口或缺血组织中触发快速的新血管形成反应，而特定位点的EPC招募是特别缺乏糖尿病。为了验证这一假设，我们计划进行实验，以实现以下具体目标： 1.为了证明生长因子的动员和募集 2.确定血管生成生长因子动员和募集骨髓源性EPCs至创伤或缺血组织靶向区域的机制 3.确定EPCs通过与细胞环境相互作用协调局部血管生成反应的机制。

DESCRIPTION (provided by applicant): Diabetic patients have a defect in their ability to heal wounds and respond to ischemic stress. The mechanisms responsible for this compromised vascular regenerative capacity are poorly understood. Recently, endothelial precursor cells (EPCs) have been recognized to be recruited to sites of neovascularization. Preliminary work in our laboratory shows that diabetic mice (db/db, NOD, and streptozotocin-induced) are specifically deficient, compared to normal control mice, in their ability to mobilize and recruit endothelial precursor cells (EPCs) to wounds or ischemic limbs. An essential role for EPC recruitment in normal mice impairs both wound healing and the response to acute ischemia. This dysfunctional regenerative neovascularization in diabetic mice can be corrected by adenoviral-mediated overexpression of angiogenic growth factors, such as Angiopoietin-1 (Ang-1) which recruit EPCs that can correct diabetic wound healing impairment and the poor response to ischemia. The overall objective of our investigations is to understand the mechanisms by which EPCs are mobilized and recruited to target tissues in wound healing and in response to ischemia and understand how these mechanisms are impaired by diabetes. Our working hypothesis is that recruitment of bone marrow-derived EPCs is essential for triggering a rapid neovascularization response in a wound or ischemic tissue and that site-specific EPC recruitment is specifically deficient in diabetes. In order to test this hypothesis we plan experiments to achieve the following specific aims: 1. To demonstrate that mobilization and recruitment of growth factors 2. To determine the mechanism by which angiogenic growth factors mobilize and recruit bone marrow-derived EPCs to target areas of a wound or ischemic tissues 3. To determine the mechanisms by which EPCs orchestrate the local angiogenic response by interaction with resident cellular milieu.