PGF2α-FP受体信号通路在调控糖尿病性心肌病心肌间质纤维化中的作用

心肌间质纤维化是糖尿病心肌病(DCM)的主要病理改变，但其调控机制尚未完全阐明。我们前项NSFC发现TGF-β干预只能减轻却不能完全遏制心肌纤维化的进程。新近研究发现PGF2α-FP受体是除TGF-β外又一致肺纤维化途径。我们初步研究显示PGF2α-FP受体信号通路与心肌成纤维细胞胶原合成密切相关，但其能否通过对PI3K/Akt和PKC/Rho激酶信号通路的调控，架起胰岛素抵抗和DCM心肌间质纤维化的桥梁尚不清楚。本课题拟建立胰岛素抵抗的心肌成纤维细胞模型，探讨FP受体过表达和FP受体基因沉默对胶原合成的调节作用及信号转导机制，并证实该通路独立于TGF-β；以2型DCM FP-/-小鼠为模型，探讨PGF2α-FP受体/PKC/Rho激酶信号通路在DCM心肌间质纤维化中的作用和干预后的效果。该研究可望通过深入研究胰岛素抵抗与DCM心肌间质纤维化的共同途径，为DCM早期防治提供新的思路和靶点。

Interstitial fibrosis in the myocardium is a prominent feature of diabetic cardiomyopathy (DCM), however, the mechanism mediating fibrosis in DCM remains incompletely understood. In our previous NSFC，we have proved that antagonizing TGF-β can only alleviate but not completely prevent myocardial fibrosis. Recently, PGF2α/FP receptor signaling was found to facilitate pulmonary fibrosis independent of TGF-β. Our initial findings have shown that PGF2α-FP receptor signaling is closely related to collagen synthesis in cardiac fibroblasts, however, whether PGF2α-FP receptor signaling bridge the gap between insulin resistance and myocardial fibrosis in DCM remains unclear. We intend to establish an insulin-resistant cardiac fibroblasts model to investigate the signaling mechanism of FP receptor in regulating collagen synthesis under FP receptor gene over-expression or silencing conditions, independently of TGF-β. Then we use type 2 DCM FP-/- mice as models to explore the role of PGF2α-FP receptor/PKC/Rho kinase signaling pathway in regulating DCM myocardial interstitial fibrosis. By investigating the common pathway of insulin resistance and DCM myocardial interstitial fibrosis, the present study is expected to provide potoential therapeutic targets for early prevention of DCM.