CRTH2 在器官纤维化中的作用及机制研究

机体器官损伤后的纤维化导致器官结构破坏和功能衰退。纤维化以成纤维细胞活化并分泌以Ⅰ型胶原为主的细胞外基质为特点，但机制仍需探究。前列腺素D2受体CRTH2，主要介导Th2细胞的活化，其在纤维化中的作用并不清楚。我们发现CRTH2和LARP6在内质网上相互作用；无论是体内还是体外， CRTH2缺失都导致Ⅰ和Ⅲ型胶原合成明显增加。LARP6增加Ⅰ和Ⅲ型胶原mRNA稳定性而影响胶原蛋白合成，因此推测CRTH2在内质网上与LARP6相互作用降低胶原mRNA稳定性，调节胶原合成的稳态平衡。我们将利用CRTH2 KO小鼠探讨CRTH2在多个器官纤维化模型中的作用；通过分子生物学手段探究CRTH2与LARP6在内质网上的互作方式；利用LARP6 KO小鼠验证CRTH2在调控器官纤维化进程中的作用。该研究旨在揭示CRTH2在器官纤维化中的作用及机制，为纤维化相关疾病治疗提供新的靶点。

Fibrosis after organ damage leads to organ structural damage and functional decline. Fibrosis is characterized by the activation of fibroblasts and the secretion of type I collagen-based extracellular matrix, but the mechanism remains to be explored. CRTH2, the prostaglandin D2 receptor, mainly mediates the activation of Th2 cells, and its role in fibrosis is not clear. We found that CRTH2 interacts with LARP6 in the endoplasmic reticulum, and CRTH2 deficiency results in a significant increase in types I and III collagen synthesis both in vivo and in vitro. LARP6 affects collagen synthesis through increase typeⅠ and Ⅲ collagen mRNA stability, so we hypothesize that CRTH2 interact with LARP6 on the endoplasmic reticulum to reduce the stability of collagen mRNA and regulate the homeostasis of collagen synthesis. We will investigate the role of CRTH2 in multiple organ fibrosis models using CRTH2 KO mice; explore the interaction of CRTH2 with LARP6 on the endoplasmic reticulum by molecular biology experiments; verify the role of CRTH2 in the regulation of fibrosis progression using LARP6 KO mice. This study aims to reveal the role and mechanism of CRTH2 in organ fibrosis and provide a new target for the treatment of fibrosis-related diseases.