Molecular mechanisms involved in the control of mTORC2 activity by Ric-8B: role of GPCR-G±s-cAMP signalling pathway.

• Grant number: 23/05319-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2023
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Victor Pereira de Sá Xavier
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM

Abstract

mTORC2 is protein complex built around its catalytic center the serine/threonine protein kinase mTOR that regulates multiple biological processes in mammalian cells whose dysfunction is associated with many diseases. Despite its importance, little is known about the mechanisms of mTORC2 regulation, especially those associated with the G protein coupled receptor (GPCR) pathway. The GPCR-G±s-cAMP signaling pathway has been shown as potential regulator of mTORC2 activity in some cell types in a context-dependent manner through unknown mechanisms that still need robust experimental confirmation. In a previous study, we showed that Ric-8B, a component of the GPCR-G±s-cAMP pathway, is an important mediator of the increase in mTORC2 activity induced by fetal bovine serum (FBS) in cells in vitro through a mechanism that seems to be independent of the G±s and G²³ dimer. In this Ph.D. proposal, we will investigate how different components of GPCR-G±s-cAMP pathway interact with mTORC2 in 3 lines of investigation focusing on Ric 8B, GPCR-G±s-cAMP and the dimer G²³. For this, we will evaluate mTORC2 activity in cells with genetic and pharmacological gain and lost of function of several steps in the GPCR-G±s-cAMP pathway. We will also investigate the impact of adipocyte Ric-8B deletion in: 1- energy balance, glucose homeostasis, lipid metabolism, body temperature and thermogenic capacity in mice fed a chow or a high fat diet either acutely or chronically exposed to cold; and 2- insulin signaling, glucose uptake and lipid metabolism in brown and white adipocytes in vitro.