Endothelial Progenitor Cell Recruitment in Diabetic Mice

描述(由申请人提供)：糖尿病患者在愈合伤口和对缺血应激做出反应的能力方面存在缺陷。导致血管再生能力受损的机制还知之甚少。最近，内皮前体细胞(EPC)被认为被招募到新生血管的部位。我们实验室的初步工作表明，与正常对照组小鼠相比，糖尿病小鼠(db/db、nod和链脲佐菌素诱导的)在动员和招募内皮前体细胞(EPC)到伤口或缺血肢体的能力方面存在明显缺陷。在正常小鼠中，EPC募集的一个重要作用是损害伤口愈合和对急性缺血的反应。糖尿病小鼠的这种功能障碍的再生性新生血管可以通过腺病毒介导的血管生成生长因子的过度表达而得到纠正，如血管生成素-1(Ang-1)，它可以招募内皮祖细胞来纠正糖尿病创面愈合障碍和对缺血的不良反应。我们研究的总体目标是了解在伤口愈合和对缺血的反应中内皮祖细胞被动员和招募到靶组织的机制，并了解这些机制是如何被糖尿病损害的。我们的工作假设是，骨髓来源的EPC的募集对于在伤口或缺血组织中触发快速新生血管反应是必不可少的，而特定部位的EPC募集在糖尿病中是特别不足的。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.证明调动和招募成长因素 2.确定血管生成生长因子动员和募集骨髓来源的内皮祖细胞到创伤或缺血组织的靶区的机制 3.通过与细胞环境的相互作用，确定内皮祖细胞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.