Sox9促进急性肾损伤组织干细胞生理性修复的机制研究

Renal injury or functional failure is a serious threat to human health. How to promote the repair of renal cell injury is an important problem to be solved. Recently, it has been found that the proliferative cell 89%, which is involved in the regeneration and repair of renal injury, is composed of Sox9 positive cells, which can lead to renal fibrosis after Sox9 knockout. However, the mechanism of Sox9 positive cells and the regulation of renal injury repair is not clear. This study by living cells in vivo lineage tracing technique and cell clone analysis of Sox9 positive cells derived from renal progenitor cells or dedifferentiated epithelial cells; expression analysis and verification of Sox9 upstream regulatory genes and downstream effectors through gene; through the detection of fibroblast and single cell proteomics screening of profibrotic molecules in renal injury Sox9-/- mice, the in vivo validation, to determine the loss of Sox9 leads to cell origin and Sox9 renal fibrosis molecular mechanism of inhibition of fibrous repair. In view of the screening of Sox9 related signal molecules, the design of small molecular compounds to observe the effect of kidney injury repair. This study will clarify the underlying mechanism of Sox9 by regulating the cellular properties of tissue to promote the physiological repair of renal injury, and provide a potential therapeutic target for renal injury repair.

肾脏损伤或功能衰竭严重威胁人类健康，如何促进肾脏损伤的组织细胞生理性修复是亟待解决的重要问题。最近发现参与肾损伤再生修复的增殖细胞89%由Sox9阳性再生细胞构成，当Sox9敲除后会导致肾脏纤维化。但是Sox9阳性再生细胞来源以及促进肾损伤修复的调控机制尚不清楚。本研究拟通过体内活体细胞世系示踪及细胞克隆分析技术研究Sox9阳性细胞来源于肾小管前体细胞还是去分化上皮细胞；通过基因表达谱分析并验证Sox9的上游调控基因以及下游效应分子；通过检测Sox9-/-小鼠肾损伤后的成纤维细胞及单细胞组学技术筛选促纤维化分子，经体内外验证，确定Sox9缺失导致肾纤维化的细胞来源及Sox9抑制纤维性修复的分子机制。针对筛选的Sox9相关信号分子，设计小分子化合物观察促进肾损伤修复的效果。本研究将阐明Sox9通过调控组织细胞属性转换促进肾脏损伤生理性修复的根本机制，为肾损伤修复提供潜在治疗靶点。

肾脏损伤或功能衰竭严重威胁人类健康，如何促进肾脏损伤的组织细胞生理性修复是亟待解决的重要问题。最近发现参与肾损伤再生修复的增殖细胞89%由Sox9阳性再生细胞构成，当Sox9敲除后会导致肾脏纤维化。但是Sox9阳性再生细胞来源以及促进肾损伤修复的调控机制尚不清楚。在本报告中, 我们通过对不同高通量数据的综合分析和实验验证，确定促进AKI损伤修复的Sox9、Egr1等关键基因，这些基因在AKI的发生发展过程中起着非常重要的作用，为进一步探索AKI的新的诊断和治疗策略提供思路。AKI后Sox9表达升高，SOX9能够激活减轻AKI肾脏损伤，促进肾小管上皮细胞修复；我们进一步研究发现Sox9可以通过促进细胞增殖、减轻损伤、减轻炎症发挥促进AKI后损伤修复的作用；Egr1可以通过结合Sox9启动子促进Sox9表达，从而促进肾脏损伤修复。Sox9可以通过Wnt/β-catenin通路促进β-catenin入核发挥促进肾小管上皮修复的作用。本研究将阐明Sox9通过调控组织细胞属性转换促进肾脏损伤生理性修复的根本机制，为肾损伤修复提供潜在治疗靶点，这些结果对于AKI的治疗提供了新的策略。