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

描述（申请人提供）：出生后新生血管的形成过程在许多疾病的发病机制中起着至关重要的作用，如糖尿病视网膜病变、损伤后组织重塑、类风湿关节炎和肿瘤生长/转移。内皮细胞（ECs）及其微环境是调控血管新生的关键。然而，这一复杂过程背后的信号转导事件尚未得到很好的理解。本提案的目的是深入了解ECs中HIF11积累和新生血管形成的调控网络。Syk-/+或Syk-/+的初步遗传分析；Rac2-/+小鼠显示整合素诱导的Rac2激活和缺氧诱导的HIF11稳定需要Syk。我们假设Syk-Vav1-Rac2信号轴存在于ECs中，并通过HIF11稳定在新生血管中发挥必要作用。我们实验室的初步数据还表明，Syk的特定区域（分别是Vav和PLC3的同源结合位点，位于B连接区域的Y342和Y346）似乎参与了整合素信号传导和迁移下游的Rac2激活，而不是Rac1。我们在目的1中提出确定Syk-Rac2信号轴可能是HIF11稳定的焦点。在Aim 2中，我们建议评估Syk-Rac2信号轴在出生后新生血管中的作用。考虑到出生后新生血管的重要性，新的分子途径Syk-Vav1-Rac2信号轴的鉴定将导致创新治疗策略的发展。

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.