信号分子AIP1在VEGFR3依赖的病理性淋巴管生成中的作用和机理研究

AIP1, a novel signaling scaffolding protein, is highly expressed in the vascular endothelium during mouse development and in adult.While VEGFR2 and its ligand VEGF-A functions as master regulators of vasculogenesis and angiogenesis, VEGFR3 is critical for lymphangiogenesis.In our previous study,AIP1 modulates VEGFR3 protein expression and stability during lymphangiogenesis, uncovering that AIP1 is a novel regulator in VEGFR3 signaling. However, the regulation mechanism of AIP1 in the pathological lymphangiogenesis is largely unknown. Based on our previous research, in this project, we will define the role of AIP1 in pathological lymphangiogenesis via lymphatic-specific transgenic mice and lymphangiogenesis models. Moreover, we will dissect the mechanisms by which AIP1 regulates VEGFR3 signaling in vivo and in vitro via cell biological and biochemical approachessuch asco-Immunoprecipitation(co-IP),indirect immunofluorescence staining,fluorescence activated cell sorting(FACS) and confocal analyses.This project will not only provide a novel insight into elucidating the regulation of signaling molecule AIP1 in VEGFR-3-dependent pathological lymphangiogenesis and vascular disease,but also provide important theoretical foundation for developing a novel therapeutic target to control lymphangiogenesis-dependent cardiovascular diseases.

AIP1是一种新的信号支架蛋白，其在发育中的小鼠以及成年小鼠的血管内皮细胞中均有高表达。VEGFR2和其配体VEGF-A对血管发生和生成起着主要调节因子的作用，而VEGFR3则对淋巴管生成十分关键。我们的前期研究发现，在淋巴管生成中，AIP1调控VEGFR3蛋白的表达和稳定性，从而揭示了AIP1是VEGFR3 信号通路的一个新的调控子，但其调控的机制及在病理性淋巴管生成中的作用尚未明确。本课题拟在前期研究的基础上，通过已构建和新构建的淋巴管特异性转基因小鼠和淋巴管生成模型，分析AIP1在病理性淋巴管生成中的作用；通过免疫共沉淀、荧光激活细胞分选法（FACS）以及共聚焦等细胞生物学和生物化学的方法，体内体外探讨AIP1调节VEGFR3信号通路的机制。本研究将揭示信号分子AIP1在VEGFR3依赖的病理性淋巴管生成和血管疾病中的调控作用，为治疗淋巴管生成依赖的心血管疾病提供新的理论依据和方法。