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

描述(申请人提供)：出生后新生血管的过程在许多疾病的发病机制中起着关键作用，例如糖尿病视网膜病变、损伤后的组织重塑、类风湿性关节炎和肿瘤的生长/转移。已知内皮细胞及其微环境是调控新生血管/血管生成的关键。然而，这一复杂过程背后的信号转导事件还没有被很好地理解。这项建议的目的是深入了解内皮细胞中HIF11积聚和新生血管的调控网络。我们对Syk-/+或Syk-/+；rac2-/+小鼠的初步遗传分析表明，Syk对整合素诱导的rac2的激活和缺氧诱导的HIF11的稳定是必需的。我们推测内皮细胞中存在Syk-Vav1-rac2信号轴，并通过稳定HIF11在新生血管形成中起着特有的作用。我们实验室的初步数据还表明，Syk的特定区域(位于B连接区的Y342和Y346分别是Vav和PLC3的同源结合位点)似乎参与了整合素信号转导和迁移下游的rac2的激活，而不是rac1的激活。我们建议在我们的Aim1中确定Syk-rac2信号轴可能是HIF11稳定的焦点。在目的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，一个新的分子通路Syk-Vav1-rac2信号轴的识别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.