胰岛星状细胞和胰岛内皮细胞相互作用对胰岛功能的影响及其机制研究

我们既往研究证实，活化的胰岛星状细胞（ISC）可以促发胰岛功能损伤和胰岛纤维化，抑制ISC活化有助于维护胰岛功能，成为防止糖尿病发展的关键策略之一。然而糖尿病病理状态下ISC活化的细胞分子机制尚未完全阐明。近期有研究发现内皮功能紊乱会导致肝星状细胞活化，活化的肝星状细胞又反过来加剧内皮功能紊乱，形成恶性循环，促进肝纤维化发生发展。而我们观察到ISC与胰岛内皮细胞（IEC）在解剖结构上密切毗邻，测序结果也显示糖尿病状态下ISC内多个与血管新生及形态调控的基因发生改变。启发我们进一步探究ISC与IEC相互作用在胰岛纤维化和胰岛功能衰竭进程中扮演的角色。本研究拟离体采用接触式流动共培养、胰岛灌流等实验探讨ISC与IEC的相互作用及其对胰岛功能的影响；通过在体胰岛移植等技术探讨ISC与IEC的相互作用对移植胰岛功能的影响；初探其分子病理学机制。为防止胰岛功能衰竭提供新的理论依据和干预靶点。

Our previous studies confirmed that activated islet stellate cells (ISC) can promote islet dysfunction and fibrosis, inhibition of ISC activation protect islets function and become the key approach to prevent the progress of diabetes. However, the cellular and molecular mechanism of ISC activation in diabetes has not been fully elucidated. Recent studies have found that hepatic endothelial dysfunction lead to activation of hepatic stellate cells (HSC), activated HSC in turn exacerbate endothelial dysfunction. This vicious circle promotes the development of liver fibrosis. However, we observed that the ISC is closely located near the islet endothelial cell (IEC). Sequencing results showed the altered expression of several genes associated with angiogenesis and vascular morphology in ISC in diabetes. These inspired us to explore the role of interaction between ISC and IEC in the irreversible failure of islet function. This study will investigate the interaction between ISC and IEC under different conditions and its effect on islet function by using contact flow co-culture, islet perfusion and single islet function test in vitro. In the meantime, using islet transplantation and other experiments to explore the effect of interaction between ISC and IEC on the function of transplanted islets in vivo. It will provide a new theory for the pathogenesis of diabetes and intervention target for the prevention and treatment of diabetes.