Exploring mTOR pathway in PIEZO1 activating signaling

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Dehydrated hereditary stomatocytosis (DHS) is a hemolytic anemia characterized by alterations of shape, hydration status, and deformability of the red blood cells. DHS patients show anemia with increased red blood cell volume compared to healthy subjects, elevated hematic bilirubin concentration, and severe iron overload in the liver. DHS is caused by mutations in the PIEZO1 gene that encodes a mechanoreceptor, i.e., a channel that permits the ion passage upon activation by several mechanical stimuli, a function essential in several physiologic processes. Despite the recent advances in understanding the DHS pathogenic mechanisms, therapies for DHS patients are still lacking and DHS clinical management is mainly based on supportive care.

Based on preliminary data, we hypothesize that alterations of the mTOR pathway and in particular of its player, LAMTOR4 (a Tdark protein that is a gene/protein with still unknown functions), impair liver physiology and function in DHS thus causing iron overload.

This hypothesis will be tested in cells and in the mouse model of the disease in order to better understand the pathogenic mechanism of DHS and find new potential therapeutic approaches to correct the iron overload phenotype, a major cause of organ damage and failure in DHS patients.