内源性非受体型Tec 酪氨酸激酶调控脓毒症急性肾损伤的分子机制

Endogenous Tec tyrosine kinase has been confirmed as an important molecule of TLR4 signaling pathway, but its role in the inflammatory response is little-known. Our previous studies have shown that Tec kinase was significantly increased in the early septic acute kidney injury. Therefore, we hypothesized that the Tec kinases may be activated through TLR4 proinflammatory signaling pathways, and trigger the inflammatory response involved in sepsis acute kidney injury. In this study, we will use the CLP mice, proximal tubular epithelial cell line NRK-52E and human monocytic cell line THP-1, to investigate the relationship between the Tec kniase and septic acute kidney injury by TLR4 KO mice and gene interference techniques. Through this study, we look forward to observe whether TLR4 play a role in Tec kniase activition in septic AKI, and to find out the relationship between Tec kniase,MAPKs, NF-κB and the important proinflammatory mediator HMGB1. The implementation of this project will help to elucidate the mechanism of the inflammatory response of sepsis, kidney, and to provide new ideas and clues for the prevention and treatment of septic acute kidney injury.

非受体型Tec 酪氨酸激酶已证实为TLR4信号通路的一个重要信号分子，但它在体内炎症反应中的作用仍知之甚少。我们前期研究表明：在脓毒症急性肾损伤即早期，小鼠肾脏Tec激酶活性就明显升高。因此，我们推测Tec激酶可能通过激活TLR4促炎性信号通路，促发炎症反应，参与脓毒症急性肾损伤的发生。本项目采用CLP脓毒症小鼠模型，并以近端肾小管上皮细胞系NRK-52E 和人单核细胞株THP-1为主要研究对象，应用TLR4 KO小鼠、基因干扰等手段，观察Tec激酶与脓毒症急性肾损伤的相关性，明确其与TLR4及其下游促炎性信号通路MAPKs和NF-κB活化的关系，并研究脓毒症重要的促炎性炎性介质HMGB1与Tec 激酶活化之间的关系，深入探讨内源性非受体型Tec 酪氨酸激酶对脓毒症急性肾损伤调控的分子机制。本项目的实施将有助于阐明脓毒症肾脏炎症反应的发生机制，并为脓毒症急性肾损伤的防治提供新的思路和线索。