Samhd-1蛋白对PI3K/Akt信号通路的调控作用及其对肝脏缺血再灌注损伤的影响

Transplantation immunity is always the hot spot in clinical organ transplantation process, in which reperfusion is inevitable. Hepatic ischemia and reperfusion (I/R) is a pathophysiological phenomenon that occurs very frequently in clinical practice. More importantly，I/R is also responsible for liver injuries that often lead to poor prognosis. Many efforts are being made to investigate the pathohysiological mechanism of I/R injury and to search for strategies that will protect liver against I/R induced damage. Recent evidence has demonstrated that innate immune and inflammatory responsed, mediated by Toll-like receptors(TLRs), participate in I/R. New evidence has identified the cross-talk between TLRs signalling and the PI3K/Akt pathway. The mechanism?of the methods or new drugs, which have been applicated for resisting IRI in clinical, mostly involved the activation of PI3K signallng pathway. The molecular mechanism and significance of this interaction is the hot spot in related field. We have found that Samhd-1 protein can act on MyD88, which is an improtant intercellular adaptor protein in TLR4 signalling pathway, and Samhd-1 can also regulate the interaction between MyD88 and PI3K. Therefore, our research will study the role of Samhd-1 as a "switch"in TLR4/MyD88 signalling and PI3K/Akt pathway, especially during hepatic ischemia and reperfusion injury. Identification the molecular mechanism of the interaction between these signalling pathways may provide a new valuable target for the treatment against IRI related diseases.

肝脏缺血再灌注损伤(IRI)是肝外伤、肝移植及机体遭受重度创伤时常见的病理生理现象。其中TLR4/MyD88信号传导机制所触发的免疫炎性反应是重要的损伤机制，而PI3K/Akt通路作为调控细胞生长与存活的关键途径，参与再灌注损伤时细胞稳态维系过程。MyD88作为TLR4通路与PI3K途径中的桥梁蛋白，其在IRI中发挥的生物学效应受到人们广泛关注。揭示MyD88蛋白的细胞生物学功能及其调控机制将为临床抗IRI开拓新思路。在我们前期工作中发现Samhd-1蛋白可作用于分子MyD88，激活PI3K/Akt途径，在肝IRI中增强MyD88与PI3K蛋白相互作用，发挥维护细胞稳态的保护作用。因此，本项目拟在肝缺血再灌注过程中，解析Samhd-1作为"调节器"通过增强MyD88分子与PI3K蛋白间的相互作用，发挥提高细胞抗损伤能力、保护肝功能作用的分子机制，为临床治疗与再灌注损伤相关疾病提供新靶点。

肝脏缺血-再灌注损伤(ischemia reperfusion injure，IRI)是肝外伤、肝移植以及机体遭受重度创伤、烧伤、休克等临床常见的病理生理现象，也是许多肝缺血性疾病预 后不良的重要原因。缺血再灌注导致的细胞损伤是一个快速的级联反应，这个级联反应包括很多环节，由细胞损伤和机体的应激状态释放的信号分子所触发的免疫炎性反应是缺血再灌注损伤的重要机制之一。其中TLR4/MyD88信号传导机制所触发的免疫炎性反应是重要的损伤机制，而PI3K/Akt通路作为调控细胞生长与存活的关键途径，参与再灌注损伤时细胞稳态维系过程。MyD88作为TLR4通路与PI3K途径中的桥梁蛋白，其在IRI中发挥的生物学效应受到人们广泛关注。揭示MyD88蛋白的细胞生物学功能及其调控机制将为临床抗IRI开拓新思路。在我们前期工作中发现Samhd-1蛋白可作用于分子MyD88，激活PI3K/Akt途径，在肝IRI中增强MyD88与PI3K蛋白相互作用，发挥维护细胞稳态的保护作用。因此，本项目在肝缺血再灌注过程中，解析Samhd-1作为“调节器”通过增强MyD88分子与PI3K蛋白间的相互作用，激活PI3K/Akt保护途径，发挥提高细胞抗损伤能力、保护肝功能作用的分子机制，为临床治疗与再灌注损伤相关疾病提供新靶点。