sEH调控N-cadherin/CTF2片段的产生在淋巴管生成中的作用及机制研究

淋巴管内皮细胞在维持器官内稳态中起关键作用。申请人前期研究发现，可溶性环氧化物水解酶（sEH）介导的多不饱和脂肪酸代谢通路在血管生成及稳态中发挥重要作用(JEM 2014，Nature 2017，JCI 2019)。然而，其在淋巴管中的作用尚不清楚。预试验发现，sEH介导的DHA代谢产物19,20-DHDP促进早老蛋白presenilin 1对神经钙粘蛋白N-cadherin的切割，增加CTF2片段的产生，从而抑制淋巴管生成。我们推测sEH代谢通路可能是调控淋巴管生成的新靶点。本课题拟：1)利用全身及细胞特异性基因敲除明确sEH代谢通路及其代谢产物19,20-DHDP在淋巴管生成中的作用及机制；2)筛选新的sEH潜在活性代谢产物并阐明其作用机制；3) 利用病理模型研究以sEH代谢通路为淋巴管生成相关疾病治疗靶点的可能性。本研究将有助于发现淋巴管生成的新机制，为淋巴管相关疾病治疗提供新靶点。

Lymphatic endothelial cells play essential role in organ homeostasis. Our previous studies have demonstrated a crucial role of soluble epoxide hydrolase (sEH) mediated polyunsaturated fatty acids (PUFAs) metabolism in angiogenesis and vessel homeostasis (JEM 2014, Nature 2017, JCI 2019). However, their effect on lymphangiogenesis remain unknown. In our preliminary data we found that the genetic deletion of sEH increased lymphangiogenesis in vivo. In line with this, the sEH-derived DHA metabolite 19,20-DHDP halted lymphangiogenesis in vitro. Mechanistically, 19,20-DHDP was found to promote presenilin 1-mediated cleavage of N-cadherin and the generation of its C-terminal fragment CTF2 which regulates lymphatic gene expression. In the proposed study we will: 1) characterize the function of sEH and its PUFA metabolites, especially the 19,20-DHDP, in lymphangiognesis by using global and cell-specific knockout mice; 2) identify novel bioactive lipid mediator(s) that impact lymphangiogenesis using LC-MS/MS based PUFAs profiling and investigate the underlying mechanism(s); 3) explore the therapeutic potential of targeting sEH-mediated PUFAs generation for lymphangiogenesis related diseases. This study will reveal the function of sEH-mediated PUFAs metabolism in lymphangiognesis and provide novel insights into the understanding and treatment of lymphangiogenesis related diseases.