基于蛋白质组学研究Prpc/EGFR信号分子复合体在急性肾损伤慢性化转归中的作用及机制

随着急性肾损伤（AKI）治愈率的提高，其慢性化转归成为肾脏病学面临的巨大挑战。本课题前期研究发现：朊蛋白基因敲除（Prnp-/-）小鼠与野生小鼠相比，在缺血性损伤后，肾小管间质纤维化程度更严重；蛋白质组学研究发现：缺血再灌注肾损伤导致EGFR、DNA损伤修复反应（DDR）相关蛋白表达显著升高，而在Prnp-/-小鼠，虽然EGFR进一步上调，DDR相关蛋白却明显减少。文献报道：DDR异常导致AKI的慢性转归；EGFR信号通路可介导DDR，促进修复，然而持续活化则导致纤维化。细胞型朊蛋白（Prpc）可与EGFR结合，双向调节后者活性。由此推测：Prpc通过维持EGFR信号通路稳定，精细调控DDR，促进肾小管修复，抑制AKI慢性化转归。本研究拟在缺血再灌注和单侧输尿管结扎等多个肾纤维化模型，借助基因干扰、敲除、蛋白组学等技术验证该假设，阐明AKI慢性化转归调控机制，为制定防治策略提供理论依据。

With the improvement of the therapy of acute kidney injury (AKI), the chronic outcome of AKI becomes a key problem in the field of nephrology. Our previous research found that compared with wild type mice, prion protein knockout (Prnp-/-) mice showed earlier and more severe renal tubular interstitial fibrosis after ischemia-reperfusion injury. Furthermore, we found that in the late stage of ischemia-reperfusion-induced acute kidney injury, the expressions of key proteins such as epidermal growth factor receptor (EGFR) and DNA damage repair response (DDR) were significantly increased by proteome analysis. However, in Prnp-/-Mice, EGFR is further up-regulated, while DDR-related proteins are significantly down-regulated. It was reported that DDR plays an important role in the chronic outcome of AKI; renal EGFR signaling pathway can induce DDR and promote repair in the early stage of injury, but continuous activation leads to chronic outcome. In neurons, cellular prion protein (Prpc) forms multimolecular complex with EGFR, which regulates EGFR pathway activity in both directions. Thus, we hypothesize that the Prpc / EGFR signaling molecule complex can inhibit the chronic outcome of AKI by mediating DDR pathways. This study intends to test this hypothesis in multiple renal fibrosis models such as ischemia-reperfusion and unilateral ureteral obstruction to clarify the regulatory mechanism of chronic renal injury prognosis by using siRNA, knockout, proteomics and other techniques. This study will lay foundation for exploring prevention and treatment strategies of chronic kidney diseases.