CLPP通过抑制能量代谢参与肾小管细胞损伤和纤维化的研究

肾纤维化是各种肾脏疾病进行性发展的共同病理特征，起因于肾脏固有细胞损伤。由于技术限制，既往研究主要基于肾组织混合细胞基因表达分析，不同细胞类型相互干扰而掩盖关键分子过程。本研究基于肾脏单细胞测序，设计了一种研究策略鉴定肾小管不同细胞类型在UUO模型中表达变化的基因，通过生信分析鉴定了它们上游调控因子CLPP。由于CLPP靶向抑制的26个基因主要参与能量代谢，我们提出肾小管损伤新机制：CLPP活化抑制了参与能量代谢的重要基因的表达，导致肾小管细胞供能不足，促进细胞损伤和肾脏纤维化。本研究将利用CLPP敲除和过表达等体内体外模型对这一假说进行验证，并将检测CLPP在各种肾脏疾病临床标本中的变化，并与临床指标进行相关性分析，探讨其临床转化意义。本研究有望发现肾脏损伤和纤维化的关键分子，为肾脏疾病防治提供新靶标；我们设计的基于单细胞测序数据的研究策略也将为本领域提供一种重要研究手段。

Renal fibrosis is a common pathological feature of the progressive development of various renal diseases, which is caused by the damage of intrinsic renal cells.Due to technical limitations, previous studies were mainly based on gene expression analysis of mixed cells in kidney tissue, with different cell types interfering with each other to mask key molecular processes.In this study, based on renal single cell sequencing, a research strategy was designed to identify the genes that were expressed differently in different renal tubules in the UUO model, and their upstream regulatory factor CLPP was identified by bioinformatic analysis.Since 26 genes targeted by CLPP are mainly involved in energy metabolism, we propose a new mechanism of renal tubule injury: CLPP activation inhibits the expression of important genes involved in energy metabolism, leading to insufficient energy supply of renal tubule cells, promoting cell damage and renal fibrosis.This study will use in vivo and in vitro models such as CLPP knockout and overexpression to verify this hypothesis. The changes of CLPP in clinical specimens of various renal diseases will be detected, and the correlation analysis with clinical indicators will be conducted to explore its clinical translational significance.This study is expected to identify the key molecules involved in kidney injury and fibrosis and provide a new target for the prevention and treatment of kidney diseases.Our research strategy based on single cell sequencing data will also provide an important research tool in this field.