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.