Metabolic deregulation, genome instability, and the progression of chronic kidney disease

慢性肾脏病（CKD）是一种全球性的健康负担，影响10-15%的人口。此外，CKD已被确定为心血管死亡的主要风险因素。CKD可由各种不同的肾脏疾病引起，其特征在于功能性肾小管的丧失、肾微血管的丧失和进行性纤维化。最近的临床、遗传和实验证据表明，肾小管上皮细胞的基因组不稳定性是肾纤维化和CKD进展的关键致病因素。值得注意的是，在CKD的肾外细胞中也观察到DNA损伤的积累，表明CKD对基因组稳定性的全身性影响。我们假设未解决的DNA损伤的积累以及由此产生的转录组学、表观遗传学和代谢变化形成恶性循环，并代表肾纤维化和CKD进展的主要驱动力。因此，该项目的首要目标是分析CKD发病机制中基因组不稳定性与转录和代谢失调的相互作用。基于完善的小鼠模型，我们的目标是获得对基因组不稳定性作为肾脏疾病驱动因素的机制见解。为此，我们将描述肾脏DNA损伤引起的代谢、转录组和表观遗传改变，并分析饮食干预对疾病进展的影响。具体而言，我们将（1）分析DNA修复缺陷如何影响基因组稳定性，导致肾纤维化和终末期肾衰竭，（2）解决参与肾脏基因组维持的信号网络，（3）研究代谢改变与肾功能丧失和疾病进展中基因组不稳定性之间的相互作用。最终，我们的目标是为未来的临床应用开发针对肾基因组不稳定性和预防CKD的策略。

Chronic kidney disease (CKD) is a global health burden that affects 10-15% of the population. Moreover, CKD has been identified as a major risk factor for cardiovascular mortality. CKD can result from various different renal disorders and is characterized by loss of functional renal tubules, loss of renal microvasculature, and progressive fibrosis. Recent clinical, genetic and experimental evidence suggested genome instability in renal tubular epithelial cells as a critical pathogenic factor in renal fibrosis and CKD progression. Notably, accumulation of DNA damage has also been observed in extra-renal cells in CKD, indicating systemic effects of CKD on genome stability. We hypothesize that the accumulation of unresolved DNA damage and the resulting transcriptomic, epigenetic and metabolic changes form a vicious circle and represent the main driving forces of renal fibrosis and CKD progression. Therefore, the overarching aim of this project is to analyze the interplay of genome instability and transcriptional and metabolic deregulation in the pathogenesis of CKD. Based on well-established mouse models we aim to gain mechanistic insights into genome instability as a driver of kidney disease. To this end, we will characterize metabolic, transcriptomic, and epigenetic alterations caused by DNA damage in the kidney and analyze the effects of dietary interventions on disease progression. Specifically, we will (1) analyze how defects in DNA repair may affect genomic stability causing renal fibrosis and end-stage-renal failure, (2) address signaling networks involved in genome maintenance in the kidney, and (3) study the interplay between altered metabolism and renal function loss and genomic instability in disease progression. Ultimately, we aim to develop strategies for future clinical applications targeting renal genome instability and preventing CKD.