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缺血应激反应能力方面存在缺陷。造成这种血管再生能力受损的机制尚不清楚。最近，内皮前体细胞（EPCs）已被认为是招募到新血管形成的部位。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）在动员和募集内皮前体细胞（EPCs）到伤口或缺血肢体的能力方面存在特异性缺陷。在正常小鼠中，EPC的募集对伤口愈合和对急性缺血的反应都有影响。这种功能失调的再生新生血管在糖尿病小鼠中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 （ang1）的过度表达来纠正，血管生成素-1招募内皮祖细胞，可以纠正糖尿病伤口愈合损伤和对缺血的不良反应。我们研究的总体目标是了解EPCs在伤口愈合和缺血反应中被动员和招募到靶组织的机制，并了解这些机制如何被糖尿病损害。我们的工作假设是，骨髓来源的EPCs的募集对于触发伤口或缺血组织的快速新生血管反应是必不可少的，并且在糖尿病中特异性的EPCs募集是特别缺乏的。为了验证这一假设，我们计划实验以实现以下具体目标：

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.