Investigating cancer metabolism and its potential for therapeutic intervention

项目摘要 癌细胞以不同于正常细胞的方式使用燃料，如葡萄糖和谷氨酰胺。的确，这改变了 代谢是几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，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。世纪前，奥托·瓦尔堡发现， 癌细胞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，这就是后来创造的“有氧”糖酵解。 他的假设已经被修改，包括TCA循环的重要性以及糖酵解作为一种手段 创造生物合成的基础，比如脂类和核酸。TCA循环整合葡萄糖， 氨基酸和脂质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。如果我们能够理解 癌细胞如何调节这些过程，也许我们可以确定新的干预目标。这项建议 有两个主要目标。第一个重点是了解癌症中代谢改变的作用， 新的治疗目标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 我的论文项目的基础，重点是磷酸烯醇式丙酮酸羧激酶（PEPCK）， 酶因其在植物异生中的作用而众所周知。先前的研究还表明，PEPCK是一个关键的调节因子， TCA循环通量。我们的实验室已经证明了PEPCK的作用，它将代谢通量和合成代谢途径联系起来， 癌细胞增殖目的2建议将这些研究扩展到结肠癌发生模型， 了解PEPCK的亚细胞定位在代谢和生长中的作用。最后，Aim 3提出 我将如何扩大我的博士前培训，以成为一个成功的癌症研究，重点是 癌症代谢通过完成这些目标，我相信通过这种培训机制，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.