Myc-induced expression of glutamine synthetase

项目摘要 这是一个F99/K 00应用程序，将包括我的博士前和博士后培训。我所描述 我的研究经验与我在Aim 1完成的论文工作有关。我的训练计划 目标2强调了要完成的论文工作和要获得的技能。最后，目标3描述了我的 博士后研究金阶段的未来培训计划。我在博士前培训期间的研究课题 (F99)期间的重点是了解调节谷氨酰胺代谢的癌基因Myc。Myc 已知癌蛋白驱动能量代谢的重编程以满足能量消耗的需要， 大分子生物合成和癌细胞中的废物处理。Myc水平升高的癌症表现出 对谷氨酰胺的依赖性增加，这归因于谷氨酰胺酶（GLS），该酶催化 谷氨酰胺脱氨为谷氨酸盐，为三羧酸（TCA）循环提供燃料。有趣的是，我的担保人 博士宗伟星的实验室最近发现Myc可以诱导谷氨酰胺合成酶的表达 (GS)催化GLS逆反应的酶，以促进谷氨酰胺的从头合成 谷氨酸盐和氨我的初步数据表明，异位GS表达导致升高， 谷氨酰胺，用于核苷酸合成，必需氨基酸的摄取，增加细胞 生长/增殖/存活和肿瘤发生。这些数据促使形成的假设，即GS是 一种Myc驱动的肿瘤发生的关键介质，通过产生谷氨酰胺来满足对 谷氨酰胺的作用。提出了三个具体目标来检验这一假设：1）确定代谢 GS在Myc激活背景下的作用; 2）研究在Myc诱导下GS的生物学后果; 3） 探讨GS在体内的作用。该项目的完成将揭示一种新的机制， Myc促进癌细胞代谢的重新编程，并将有助于将GS确立为治疗靶点。 这项研究也将为我提供一个独特的机会，接受一流的培训，在这两个致癌信号 和癌细胞代谢，这将在很大程度上帮助我过渡到博士后阶段（K 00）， 这是实现我的职业目标，成为一名独立的癌症生物学家的重要一步。

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.