ESR 7: The divergent role of EGF and TGF-a in chronic kidney disease: towards new therapeutic targets
Supervisor: Fabiola Terzi
PhD Student: Marta Falco
The molecular pathways underlying the progression of Chronic Kidney Disease (CKD), a major public health burden, are still poorly elucidated. Among the possible candidates, epidermal growth factor receptor (EGFR) seems to play an important role. EGFR pathway is activated by 7 ligands; remarkably, our Lab has recently discovered that the nature of the ligand determines the fate of injured kidneys towards compensation or deterioration. In fact, we observed that the inactivation of TGF-alpha protects kidney from renal deterioration, whereas that of EGF increases lesion development. In particular, we identified Kinase I as a specific EGFR partner upon TGF-alpha activation. Importantly, we discovered that these data are relevant to humans. The aim of the project is to elucidate the molecular pathways underlying the progression of CKD in order to uncover new potential therapeutic approaches. Specifically, the objective is to determine the molecular mechanisms and genetic networks mediate by TGF-alpha-Kinase I and identify new therapeutic targets for this disorder.
CKD has become a very important issue in recent years due to its social and economics implication and most important to its increasing frequency. This disorder is characterized by progressive impaired renal function to end stage renal disease that occurs when a critical number of functional nephrons has been lost. Despite CKD represents a worldwide concern, the mechanisms of the disease progression are not completely clarified.
Several evidences suggest that EGFR has a key role in the development of renal lesions. EGFR belongs to the ErbB receptor tyrosine kinase family and participates to various important cellular functions such as proliferation, growth, survival, and migration. Activation of EGFR is regulated by its ligands, members of a family of growth factors, including EGF and TGF-α. Previous studies showed that EGFR pathway is critically involved in CKD progression. In fact, it can mediate cellular mechanisms may result in either a beneficial or detrimental outcome during CKD: EGF has a beneficial effect, on the contrary, TGF-α has a detrimental effect. In this context, our Lab has identified Kinase I, a molecule specifically recruited by EGFR upon TGF-alpha activation, that could be potentially used as a drug target in CKD therapies.
The specific objectives of the project will be to combine in vivo and in vitro models to:
- characterize the cellular events triggered by Kinase 1 in renal epithelial cells
- identify potential signaling pathways and genetic networks mediated by Kinase I, by using, unbiased phosphoproteomic assay and RNA sequencing analysis
- uncover potential novel Kinase I targeted therapies
- translate the results to human.
- Characterization of the molecular mechanisms that account for detrimental effect mediates by TGF alpha;
- Identification of the genetic networks responsible for the specific effect of Kinase I;
- Identification of pharmacological compounds able to prevent CKD progression by selectively blocking TGF-alpha signaling.