Research

Overview

Keywords: Cell growth and proliferation, nutrient metabolism, cancer metabolism, signal transduction, mTOR signaling, T-cell development and signaling, thymus, T-cell receptor, immunometabolism, stress response, proteostasis, dietary intervention, hexosamine biosynthesis pathway, glycosylation, glycobiology

Cell growth and proliferation are dependent on nutrient metabolism. Disruption of metabolic homeostasis underlies aging and a number of pathological conditions. My research aims to define how metabolism is controlled by signaling pathways during normal and diseased states. We focus on the mechanistic target of rapamycin (mTOR) signaling pathway and its role in controlling various metabolic processes. We are interested in understanding mTOR-dependent nutrient utilization and metabolic reprogramming in a tissue microenvironment.

Currently, we are using mouse models to address how metabolic reprogramming via mTOR signaling impacts T-cell development, generation of T-cell immune responses and lymphomagenesis. We are also using cellular models to understand basic mechanisms of mTOR regulation, in particular mTOR complex 2 (mTORC2). We are leveraging our expertise in mTOR signaling and metabolism to develop more effective therapeutic strategies for cancer, other metabolic-related disorders and aging.

What is mTOR?

mTOR stands for mammalian or mechanistic target of rapamycin. Rapamycin is a naturally occuring compound (drug) that was originally isolated from soil samples in the island of Rapa Nui (Easter Island). It was found to have immunosuppressive activity and is being developed as an anti-cancer drug. Furthermore, this drug has been shown to prolong lifespan in lower organisms and mice.

 

In the lab, rapamycin has been instrumental in understanding the functions of mTOR. TOR in yeast was the first to be identified using this drug. In this organism, TOR controls the growth machinery in response to the presence of nutrients. This function of yeast TOR has been conserved through evolution and mTOR is now known as a central controller of growth. Since multicellular organisms rely on other environmental or extracellular inputs for growth, such as growth factors, cytokines, and hormones, mTOR can process these different inputs to control cell and organismal growth.

mTOR is a protein kinase (enzyme) that is regulated by signals coming from nutrients (such as amino acids) and growth factors/hormones (such as insulin). It forms protein complexes by associating with other proteins. So far, there are two mTOR protein complexes (mTORC1 and mTORC2). Association with distinct partners can regulate its activity and function. mTOR, along with its partners, can also undergo modifications (eg phosphorylation) that can alter its activity. We are trying to understand how the mTOR protein complexes are regulated by nutrients and insulin. When there are sufficient growth signals, the mTOR pathway is activated; anabolic processes are augmented along with increased gene transcription, protein production to promote cell growth and proliferation. One of the main interests in our lab is to understand how the mTOR pathway orchestrates metabolic processes.

Why is mTOR relevant for cancer and other metabolic disorders?

Cancer cells have aberrant growth and metabolism. Most of the genes that encode proteins that are part of the mTOR pathway, including mTOR itself, have been found to be mutated in a number of cancers. Mutation of these genes lead to deregulated activity of the proteins involved in the mTOR pathway. Increased activity of the mTOR pathway is like an “engine gone out of control”. The cellular engine cranks up the fuel (nutrient) supply to support uncontrolled growth and proiferation. How can we stop the fuel supply? Since all living cells in our body require fuel, how can we specifically stop the fuel supply of cancer cells? How do the different cells in a tissue utilize specific nutrients? Can we manipulate the diet to prevent cancer and improve therapeutic strategies? These are some of the questions we address in our lab.

How does mTOR control metabolism?

mTOR controls various aspects of cellular metabolism including nutrient uptake, catabolism and anabolism. Our lab has identified how mTORC2 controls a key metabolic enzyme, GFAT1 (GFPT1) that is crucial for the de novo hexosamine biosynthetic pathway (HBP). The HBP produces a key metabolite, UDP-GlcNAc, that is utilized for glycosylation of proteins, lipids, and nucleic acids. Glycosylation is a type of macromolecule modification that alters the structure, stability, and/or function of macromolecules. Defects in glycosylation are found in various diseases including immune dysfunction, neurological disorders, cancer, and other metabolic disorders. Our lab is studying how nutrients and mTORC2 impact the HBP, how deregulation of the HBP lead to defects in immunity and how we can target mTOR signaling and the HBP more effectively by dietary manipulation and pharmacological interventions.

 

Current Research Projects:

Metabolic reprogramming during early T-cell development and lymphomagenesis (in collaboration with Dr. Guy Werlen)

Regulation of mTOR complex 2

Regulation of mTORC2 by RNA binding proteins (in collaboration with Dr. Gary Brewer)

Targeting mTOR signaling pathway in stroke (in collaboration with Drs. Harvey Weiss and Oak Chi)