Role of Syk and Rac2 in regulation of HIF1alpha and neovascularization.

描述（由申请人提供）：出生后新生血管形成过程在许多疾病的发病机制中起关键作用，例如糖尿病视网膜病变、损伤后组织重塑、类风湿性关节炎和肿瘤生长/转移。内皮细胞（endothelial cells，ECs）及其微环境是调节新生血管形成的关键。然而，这一复杂过程背后的信号转导事件还没有得到很好的理解。本提案的目的是深入了解内皮细胞中HIF 11积累和新血管形成的调控网络。我们对Syk-/+或Syk-/+; Rac 2-/+小鼠的初步遗传分析揭示了Syk对整合素诱导的Rac 2活化和缺氧诱导的HIF 11稳定的需要。我们推测Syk-Vav 1-Rac 2信号轴存在于EC中，并通过HIF 11稳定化在新生血管形成中发挥专性作用。我们实验室的初步数据还表明，Syk的特定区域（B接头区的Y342和Y346，它们分别是Vav和PLC 3的同源结合位点）似乎参与Rac 2的活化，而不是整合素信号传导和迁移下游的Rac 1。在我们的目标1中，我们提出确定Syk-Rac 2信号轴是HIF 11稳定的可能焦点。在目的2中，我们提出评估Syk-Rac 2信号轴在出生后新生血管形成中的作用。考虑到出生后新生血管的重要性，一个新的分子途径，Syk-Vav 1-Rac 2信号转导轴的鉴定，将导致创新的治疗策略的发展。

DESCRIPTION (provided by applicant): The process of postnatal neovascularization plays a crucial role in pathogenesis of numerous diseases e.g. diabetic retinopathy, tissue remodeling upon injury, rheumatoid arthritis and tumor growth/metastasis. It has been known that endothelial cells (ECs) and its micro environment is the key for regulation of neovascularization/angiogenesis. However, the signal transduction events underlying this complex process are not well understood. The objective of this proposal is to gain insight the regulatory network in ECs for HIF11 accumulation and neovascularization. Our preliminary genetic analysis of Syk-/+ or Syk-/+; Rac2-/+ mice reveal a requirement of Syk for integrin induced activation of Rac2 and hypoxia induced stabilization of HIF11. We hypothesize that Syk-Vav1-Rac2 signaling axis exists in ECs and plays an obligate role in neovascularization via HIF11 stabilization. Preliminary data from our laboratory also suggest that specific region of Syk (Y342 and Y346 at B linker region, those are cognate binding sites for Vav and PLC3 respectively) appear to be involved in the activation of Rac2 but not Rac1 downstream of integrin signaling and migration. We propose in our Aim1 to determine Syk-Rac2 signaling axis a possible focal point for HIF11 stabilization. In Aim 2 we propose to evaluate the role of Syk-Rac2 signaling axis in postnatal neovascularization. Considering the importance of postnatal neovascularization, the identification of a novel molecular pathway, Syk-Vav1-Rac2 signaling axis, will result in the development of innovative therapeutic strategies.