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Myc-induced expression of glutamine synthetase

Myc 诱导的谷氨酰胺合成酶表达

基本信息

批准号：
9355574
负责人：
Alex Bott
金额：
$ 3.8万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-21 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355574
关键词：
Amino Acids Ammonia Anabolism Applications Grants Biochemistry Biological Cancer Biology Cell Proliferation Cell Survival Cells Cellular Metabolic Process Cellular biology Citric Acid Cycle Consumption Critical Thinking Data Deamination Dedications Dependency Disease Elements Energy Metabolism Enzymes Essential Amino Acids Exhibits FRAP1 gene Faculty Fellowship Future Genetic Glutamate-Ammonia Ligase Glutamates Glutaminase Glutamine Goals Growth Human Laboratories MYC gene Malignant Neoplasms Manuscripts Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular Molecular Biology Mouse Cell Line Mus Nucleotide Biosynthesis Nutrient Oncogenic Oncoproteins Oxidation-Reduction Pharmacology Phase Play Positioning Attribute Reaction Refuse Disposal Regulation Research Research Personnel Research Project Grants Role Signal Transduction Supporting Cell Testing Therapeutic Thymine DNA Glycosylase Time Tissues Training Tricarboxylic Acids Universities Work Writing Xenograft procedure addiction aerobic glycolysis anticancer research c-myc Genes cancer cell cancer genetics career cell growth cell type deprivation design experience experimental study in vivo macromolecule metabolomics mouse model neoplastic notch protein novel nucleotide metabolism overexpression post-doctoral training pre-doctoral promoter response skills small hairpin RNA targeted cancer therapy therapeutic target tool transcription factor tumor growth tumor metabolism tumor xenograft tumorigenesis uptake

项目摘要

Project Summary 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.

项目总结