ROCK1/2调节淋巴管纽扣状连接和吸收功能的作用及机制研究

目前淋巴管在体液稳态维持和脂质代谢中的关键作用已获得广泛关注。纽扣状连接是近年新发现的淋巴管系统特有的细胞间连接类型，由毛细淋巴管上的淋巴管内皮细胞形成，对淋巴管执行吸收脂肪和组织间液的生理功能至关重要，但维持其特殊结构的基因和机制不明。我们率先发现Rho相关激酶（ROCK）的抑制剂可改变纽扣状连接形态和功能。进一步预实验结果提示ROCK的两个亚型ROCK1/2可能是淋巴管内皮细胞中维持纽扣状连接的关键基因。以此为基础，本项目拟运用淋巴管体内外研究体系，系统研究：(1)ROCK1/2在淋巴管内皮细胞中对纽扣状连接形态结构的调节作用；(2)生理及病理状态下ROCK1/2对淋巴管吸收功能的影响；(3)ROCK1/2调控纽扣状连接结构和功能的下游分子机制，旨在揭示控制纽扣状连接形成和淋巴管功能的新机制，为找到针对淋巴管吸收功能失调疾病的精准疗法奠定理论基础。

Currently, the critical roles of lymphatic system in fluid homeostasis and lipid metabolism have been widely recognized. The button-like junctions are recently newly discovered specialized cell-cell junctions formed by lymphatic endothelial cells of lymphatic capillaries and are crucial for the execution of the physiological functions of lymphatic vessels, including uptake of lipids and interstitial fluids. However, the genes that sustain the special morphology of button-like junctions and the underlying mechanisms remain largely unclear. We have previously shown that a Rho-associated kinase (ROCK) inhibitor alters the morphology and function of button-like junctions. Further preliminary studies indicate that ROCK1/2, the two isoforms of ROCK, may play a critical role in the maintenance of button-like junctions in lymphatic endothelial cells. Based on these results, we will take advantage of the in vivo and in vitro models of lymphatic vessels to investigate 1) the role of ROCK1/2 in the regulation of button-like junction morphology and structure in lymphatic endothelial cells; 2) the effect of ROCK1/2 on lymphatic uptake function under physiological and pathological conditions; and 3) the downstream molecular mechanism by which ROCK1/2 modulates button-like junction structure and function, with the goal to reveal novel mechanism in the control of button-like junction formation and lymphatic functions and to provide experimental evidences for identifying potent therapeutic targets against disorders associated with lymphatic uptake dysfunction.