This is a F99/K00 application which will encompass my predoctoral and postdoctoral training. I have described my research experience which pertains to my completed dissertation work in Aim 1. My training plan for dissertation work to be completed and skills to be gained are highlighted in Aim 2. Finally, Aim 3 describes my future training plans for the postdoctoral fellowship phase. My topic of research during my predoctoral training (F99) period is focused on understanding the regulation of glutamine metabolism by the oncogene Myc. Myc oncoprotein is known to drive reprogramming of energy metabolism to meet the needs of energy consumption, macromolecule biosynthesis, and waste disposal in cancer cells. Cancers with elevated level of Myc exhibit an increased dependency on glutamine, which has been attributed to glutaminase (GLS), the enzyme catalyzing the deamination of glutamine into glutamate to fuel the tricarboxylic acid (TCA) cycle. Intriguingly, my sponsor Dr. Wei-Xing Zong?s laboratory recently found that Myc can induce the expression of glutamine synthetase (GS), the enzyme that catalyzes the reverse reaction of GLS, to promote the de novo synthesis of glutamine from glutamate and ammonia. My preliminary data demonstrate that ectopic GS expression leads to elevated glutamine that is used for nucleotide synthesis, uptake of essential amino acids, increased cell growth/proliferation/survival, and tumorigenesis. These data prompt the formation of the hypothesis that GS is a critical mediator of Myc-driven tumorigenesis by generating glutamine to meet the increased demand of glutamine in cancer cells.
Three specific aims are proposed to test this hypothesis: 1) Determine the metabolic role of GS in the context of Myc activation; 2) Study the biological consequences of GS under Myc induction; 3) Explore the role of GS in vivo. Accomplishment of this project will unravel a novel mechanism through which Myc promotes reprogramming of cancer cell metabolism, and will help to establish GS as a therapeutic target. This study will also offer a unique opportunity for me to receive top-notch training in both oncogenic signaling and in cancer cell metabolism, which will largely help me to transition to the postdoctoral phase (K00) which is an instrumental step to achieve my career goal to become an independent cancer biologist.
This project is designed to study the molecular regulation and function of glutamine synthetase in cell metabolism and tumorigenesis in Myc-driven cancer. If successful, this study will provide understanding of a novel mechanism through which Myc regulates cell metabolism and oncogenesis, and will help to establish GS as a novel target for cancer therapy.