My research project

Outgrowths, tumors, cysts, renal, cardiac neurological defects and a compromised immune system are present in mTORopathies. Somatic mutations in RagC have been linked to fatal dilated cardiomyopathy, and various members of the MENTOR (Efeyan, Pende, Ballabio) have described life threatening pathologies in the kidney, in agreement with those observed in familial mTORopathies (Birt Hogg Dube and TSC). We have previously generated knock-in mice expressing activating mutations in RagA that mimics several features of mTORopathies. We have also KI activating mutations in RagC originally found in B-cell lymphomas, and such systemic expression of RagC mutations result in alterations in the heart that are consistent with dilated cardiomyopathy. In addition, these mice also exhibit multi-organ features of accelerated aging, and importantly for this proposal, progressive inflammation and other phenotypic alterations in RagC-mutant kidneys. Understanding the cellular and molecular underpinnings of these pathologies is somehow obscured by the pleiotropic effects that RagC mutations have on immune cells and on inflammation. We want to dissect the effects that are cell-autonomous in the kidney and heart parenchyma, thus mirroring somatic mutations in cells from these two organs, and in contrast to those systemic effects secondarily driven by deregulation of inflammatory cells. This will be followed by the dissection of the molecular mechanisms underlying such alterations by means of primary cultures and organoids derived from these models under hypothesis-driven and unbiased – omics interrogation. We will then test genetic epistasis and selected compounds in vitro and in vivo.