Understanding metabolic flux and the control of mammalian cell growth

描述(申请人提供)：癌症是一种细胞生长不受控制的疾病，在这种疾病中，细胞获得突变，导致正常组织发育之外的细胞增殖。在过去的30年里，分子的进步已经表征了许多在癌症进展过程中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会导致代谢网络的严重改变。与正常组织相比，肿瘤中葡萄糖代谢的差异已经被注意到超过70年；然而，其起源、后果、癌症的特异性和干预的原则却知之甚少。我们对癌细胞新陈代谢的理解受到代谢途径和改变这些途径的遗传异常之间相互作用的巨大复杂性的挑战。取得进展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的技术，细胞和组织中的大量小分子，以及可以分析许多同时相互作用的影响的数学模型。投资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，并导致创新疗法的出现。我提议的研究集中在癌细胞生长和发育的这个中心问题上，并利用植根于系统生物学的计算方法的应用，以及使用高通量技术，如基于质谱学的代谢组学，来了解导致癌细胞和原发肿瘤无调控生长和新陈代谢改变的机制。在我的博士后工作中，我发现了两条在细胞快速增殖和肿瘤发展过程中的新陈代谢途径。这些研究将代谢组学技术与我在博士后培训中学到的技术结合起来，涉及细胞生物学、生物化学和遗传学。一条途径涉及另一条葡萄糖摄取途径，该途径将分解代谢的葡萄糖代谢与能量代谢分离。另一种途径是通过糖酵解中间产物将糖酵解通量转移到合成代谢中。进一步的遗传学研究证实，在人类癌症的发展过程中，这种途径是被选择的。在指导阶段的博士后培训剩余时间里，我将继续这些项目。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明确的生物学问题，以了解葡萄糖代谢在癌症中的作用。我之前接受的系统生物学培训，以及目前在一家领先的癌症生物学和信号转导实验室接受的培训，提供了一套非常适合解决这一问题的技能。

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.