Chemokine Modulation of Endothelial Cell Behavior

描述（由申请人提供）：我建议阐明伤口愈合过程中调节血管形成的机制。血管生成是早期伤口愈合的重要事件，将营养物质、氧气和炎性细胞（以及可能的前体干细胞）递送到伤口部位。然而，在修复的解决阶段，大多数新血管内旋。过多的脉管系统阻止真皮成熟为相对无细胞的屏障。虽然许多组织正在研究新血管的形成，但很少有人关注限制新血管形成的停止信号。在我导师的实验室里，以前的工作确定了一类趋化因子，它们在伤口愈合的解决阶段作为纤维增生的停止信号。对于这项研究，我假设这些ELR阴性CXC趋化因子IP-10和/或Mig也可以防止过度血管化。我将首先验证如文献中所报道的那样，内皮细胞迁移受到抑制。然后，我将确定IP-10和/或Mig抑制内皮细胞迁移/增殖的途径。我还将研究在伤口愈合的不同阶段，微血管内皮细胞上的CXC趋化因子受体3是否上调。最后，我们将确定在伤口愈合过程中诱导细胞产生和释放IP-10和Mig的信号。这项研究将提供潜在的新目标，以促进或限制组织中的血管发育，并有助于我们的能力，工程组织与适当的微血管。

DESCRIPTION (provided by applicant): I propose to elucidate the mechanisms that regulate vascularization during would healing. Vasculogenesis is an important event of early wound healing, delivering nutrients, oxygen and inflammatory cells (and possibly precursor stem cells) to the wound site. However, during the resolving phase of repair, most of the new vessels involute. Excessive vasculature prevents the maturation of the dermis to a relatively acellular barrier. While many groups are examining the initiating of new vessels, few are looking at the stop signals that limit the neovasculature. Previous work in my mentor's laboratory identified a class of chemokines that act as stop signals for fibroplasia during the resolving phase of wound healing. For this study, I hypothesize that these ELR-negative CXC chemokines IP-10 and/or Mig also prevent excessive vascularization. I will first verify that endothelial cell migration is inhibited as reported in the literature. Then I will identify the pathway(s) through which IP-10 and/or Mig inhibits endothelial cell migration/proliferation. I also will investigate whether the CXC chemokine receptor 3 is upregulated on microvascular endothelial cells at different stages of wound healing. Lastly, we will determine the signals that induce the production and release of IP-10 and Mig from cells during wound healing. This study will provide potential new targets to promote or limit vascular development in tissue and contribute to our ability to engineer tissues with appropriate microvasculature.