Deciphering the molecular basis of alström syndromegenotype-phenotype correlations and a multi-omics approach to tgf-β pathway regulation

Zusammenfassung

This thesis project will deal with the ALMS1 gene and its implication in the TGF-B; pathway. Recent studies in our group determined that this protein could be interacting with the TGF-B; pathway, one of the main signal transduction pathways, and that it has already been extensively studied in other diseases, such as cancer, but little described in this disease. Deregulation in the TGF-B; pathway is related to the development of fibrosis, which can occur in two independent ways: the canonical pathway (SMAD 2/3) or non-canonical pathway (p38 / MAPK). The preliminary results of our group indicate that the reduction of the levels of ALMS1 decreased the magnitude of the signaling, in addition to producing a reduction of the rapid canonical response capacity to the stimulation of the TGF-B; and BMP pathways, as well as in the case of signaling mediated by pERK1 / 2 associated with the TGF-B; pathway (while stimulating the BMP pathway, a non-canonical response of lesser magnitude was observed but without affecting the duration thereof). This project will focus on clarifying whether fibrosis production in Alström patients occurs through the canonical Smad-dependent pathway or a non-canonical pathway such as the P38 / MAPK pathway.