Understanding metabolic flux and the control of mammalian cell growth

描述（由申请人提供）：癌症是细胞生长不受控制的疾病，其中细胞获得突变，导致细胞增殖超出正常组织发育的范围。过去30年的分子进展已经表征了许多在癌症进展期间改变的信号转导途径和基因转录网络。这些网络的异常调节总是导致代谢网络的总体改变。70多年来，人们一直注意到肿瘤中葡萄糖代谢与正常组织中葡萄糖代谢的差异;然而，对肿瘤的起源、后果、癌症特异性和干预原则知之甚少。我们对癌细胞代谢的理解受到代谢途径和改变这些途径的遗传畸变之间相互作用的巨大复杂性的挑战。进步将需要新的技术和概念框架，例如高通量代谢组学，这是一种旨在在一次测量中量化细胞和组织中大量小分子的技术，以及可以解析许多同时相互作用影响的数学模型。投入这样的努力有可能从根本上改变我们对基本癌症生物学的理解，并导致创新疗法。 我提出的研究重点是癌细胞生长和发育的这一核心问题，并利用植根于系统生物学的计算方法的应用，结合使用高通量技术，如基于质谱的代谢组学，以了解导致癌细胞和原发性肿瘤中不受调节的生长和代谢改变的机制。在我的博士后工作中，我发现了两个新的代谢途径在细胞经历快速增殖和肿瘤发展。这些研究将代谢组学技术与我在博士后培训中获得的技术相结合，涉及细胞生物学，生物化学和遗传学。一种途径涉及葡萄糖摄取的替代途径，其将分解代谢葡萄糖代谢与能量代谢解耦。另一个是糖酵解通量通过糖酵解中间体转向合成代谢。进一步的遗传学研究证实，这种途径在人类癌症的发展中被选择。我将继续这些项目在我的博士后培训的指导阶段的剩余时间。这项工作将使我能够建立一个独立的研究计划，涉及使用系统生物学技术来研究定义生物学问题，以了解葡萄糖代谢在癌症中的作用。我之前在系统生物学方面的培训以及目前在一家领先的癌症生物学和信号转导实验室的培训提供了一套独特的技能，适合解决这个问题。

DESCRIPTION (provided by applicant): Cancers are diseases of uncontrolled cell growth in which cells acquire mutations that lead to cell proliferation outside of the context of normal tissue development. Molecular advances over the past 30 years have characterized many of the signal transduction pathways and gene transcription networks that are altered during cancer progression. Aberrant regulation of these networks invariably results in gross alterations of the metabolic network. Differences in the metabolism of glucose in tumors compared to that of normal tissue have been noted for over 70 years; yet, the origins, consequences, cancer specificities, and the principles of intervention are poorly understood. Our understanding of cancer cell metabolism is challenged by the enormous complexity of the interaction between metabolic pathways and the genetic aberrations that alter these pathways. Advances will require new technologies and conceptual frameworks, such as high-throughput metabolomics, a technique that aims to quantify within a single measurement, a large number of small-molecules within cells and tissues, and mathematical models that can parse the effects of many simultaneous interactions. Investing such effort has the potential to fundamentally alter our understanding of basic cancer biology and lead to innovative therapies. My proposed research focuses on this central problem of cancer cell growth and development and utilizes the application of computational methods rooted in systems biology in conjunction with the use high-throughput technologies such as mass spectrometry-based metabolomics to understand mechanisms that lead to unregulated growth and altered metabolism in cancer cells and primary tumors. During my postdoctoral work, I discovered two novel metabolic pathways in cells undergoing rapid proliferation and tumor development. These studies combined metabolomics technology with techniques I acquired in my postdoctoral training involving cell biology, biochemistry and genetics. One pathway involves an alternate route of glucose uptake that decouple catabolic glucose metabolism with energy metabolism. The other involves the diversion of glycolytic flux into anabolic metabolism through a glycolytic intermediate. Further genetic studies established that this pathway is selected for in the development of human cancer. I will continue these projects during the remainder of my postdoctoral training in the mentored phase. This work will allow me to establish an independent research program involving using systems biology techniques to investigate define biological problems in understanding the role of glucose metabolism in cancer. My previous training in systems biology and current training in a leading cancer biology and signal transduction lab provides a skill-set that is uniquely suited to approach this problem.