Understanding the physiopathology of the progression of chronic kidney disease (CKD), a major socioeconomic burden on national health care systems, is a prerequisite for developing efficient preventive strategies. Over the last years we have characterized a murine animal model of CKD based on subtotal nephrectomy. Our studies have demonstrated that in this model, renal Iesions (fibrosis and cysts) are due to a degenerative epithelial proliferation linked to the activation of EGF receptor. In this model, right after nephron reduction there is a first wave of compensatory proliferation (CP) due to a properly organized lengthening and hypertrophy of the remaining tubular structures followed by a transient quiescent period (QP). Recently, we have demonstrated that after these initial steps, in specific sensitive mouse strains, a second wave of degenerative proliferation (DP) may lead to severe renal lesions. Our previous studies have demonstrated that DP propensity can be modulated by specific mutations indicating that distinct genetic programs underlie the development of lesions. One of the aims of this research project is to identify the molecular signature that characterizes the propensity to develop renal lesions. To this end we will analyze the transcriptome of sensitive and resistant strains during the crucial steps that follow the subtotal nephron reduction, CP, QP and DP. In parallel, we will analyze the cellular mechanisms that underlie the appearance of renal lesion including the maintenance of cilia and the orientation of cell division during the two proliferative phases. Finally, we will characterize the molecular and cellular mechanisms played by Lcn2, a key factor in the development of renal lesions that is involved in the EGF pathway activation. This research project is based on a multidisciplinary approach that involves the use of cell biology, genetics transcriptomics and proteomics. On the long term, our results should shed a novel light on the molecular mechanisms and possible therapeutic treatment of chronic nephropathies.