Investigating cancer metabolism and its potential for therapeutic intervention

项目摘要 癌细胞使用葡萄糖和谷氨酰胺等燃料的方式与正常细胞不同。事实上，这一点发生了变化 新陈代谢是多种预后工具和治疗策略的基础。我们的想法是，如果我们能 了解这些差异，然后我们就可以利用它们来区分癌细胞和 正常细胞，为治疗干预提供特异性。奥托·沃伯格在一个多世纪前发现 癌细胞更喜欢将葡萄糖转化为乳酸，即使在氧气存在的情况下也是如此，这种情况后来被称为“有氧”糖酵解。 他的假说已经被修改，包括了三氯乙酸循环和糖酵解作为一种手段的重要性 创造生物合成的积木，如脂肪和核酸。TCA循环结合了葡萄糖， 氨基酸和脂类的代谢取决于细胞的需要。此外，对肿瘤至关重要的生物合成途径 生长需要TCA循环来处理葡萄糖和谷氨酰胺衍生的碳。如果我们能理解 癌细胞如何调控这些过程，或许我们可以确定新的干预靶点。这项建议 有两个主要目标。第一个重点是了解代谢改变在癌症中的作用，并确定 治疗的新靶点。第二个是关于我从研究生到博士后的职业发展 我的最终目标是成为一名成功的独立癌症研究人员。我的第一个目标是 我的学位论文项目的基础是磷酸烯醇式丙酮酸羧酸激酶(PEPCK)，以及 酶因其在糖异生中的作用而广为人知。先前的研究还表明，PEPCK是一种关键的调节因子 TCA循环通量。我们的实验室已经证明了PEPCK的作用，它将代谢流和合成代谢途径联系在一起 癌细胞增殖。目标2建议将这些研究扩展到结肠癌发生模型以及 了解PEPCK的亚细胞定位在代谢和生长中的作用。最后，目标3提出 我将如何扩展我的博士前培训，以便成为一名成功的癌症研究人员，专注于 癌症新陈代谢。通过实现这些目标，我相信，有了这个培训机制，我将能够 成为一名独立的癌症研究者。

Project Summary Cancer cells use fuels, such as glucose and glutamine, in a different way than normal cells. Indeed, this altered metabolism is the basis for several prognostic tools and treatment strategies. The idea being, that if we can understand these differences, than we can exploit them to be able to discriminate between a cancer cell and normal cell, providing specificity for therapeutic intervention. Otto Warburg discovered, over a century ago, that cancer cells prefer to convert glucose to lactate even in the presence of oxygen, later coined ‘aerobic’ glycolysis. His hypothesis has been modified to include the importance of the TCA cycle as well as glycolysis as a means of creating biosynthetic building blocks, such and lipids and nucleic acids. The TCA cycle integrates glucose, amino acid and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. If we can understand how cancer cells regulate these processes, perhaps we can identify new targets for intervention. This proposal has two main goals. The first focuses on understanding the role of altered metabolism in cancer and identifying new targets for therapy. The second is on my career development from graduate student, to post doctoral associate and my ultimate goal of becoming a successful independent cancer researcher. My first aim is the foundation of my dissertation project which focuses on phosphoenolpyruvate carboxykinase (PEPCK), an enzyme is well known for its role in gluconeogenesis. Previous studies also show PEPCK is a key regulator of TCA cycle flux. Our lab has demonstrated a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation. Aim 2 proposes to expand on these studies to a colon carcinogenesis model as well as understanding the role of PEPCK’s subcellular localization in metabolism and growth. Finally, Aim 3 proposes how I will expand upon my pre-doctoral training in order to become a successful cancer research focusing on cancer metabolism. By completing these aims, I am confident that with this training mechanism I will be able to become an independent cancer researcher.