Deciphering molecular details of cellular sugar transport and their roles in disease

项目摘要/摘要 糖，特别是葡萄糖，是一种生物能量分子，参与了广泛的基本细胞过程。这些 代谢物及其衍生物是糖酵解途径中的重要中间体，导致ATP和 作为生物合成-分泌途径的一部分，进一步用于蛋白质和其他大分子的糖基化。 在人类中，葡萄糖被肠道细胞吸收，并被输送到血液中。血糖 浓度受到激素控制和肾脏保守的重吸收机制的严格控制。次要的 活性转运蛋白促进这些吸收/再吸收过程以及活性糖的独家输送 分子传到急诊室和高尔基体。这些功能的紊乱与许多人类疾病有关，例如 二、糖尿病。因此，了解这些动态的结构复杂性是生物医学研究的一个重要目标 传送者。 在我作为独立研究员的15年任期内，我的实验室创造了许多实验第一--第一 钠葡萄糖转运体的晶体结构，电压依赖阴离子通道的第一晶体结构， 并首次使用这些坐标来描述它们的生物化学和生物物理特性。过去的五年是 对我的实验室来说是非常有成效的。我们用不同构象的新结构补充了这些原始结构 并结合它们的生物物理特征来努力阐明它们的运输机制。这些发现有 对我们对相关疾病的集体理解和对药物开发的援助的直接影响。这是已经制作好的 可能是因为我的长期R01由NIGMS资助，目前已进入第14个年头。另外，我最近 授予新的R01，旨在阐明核苷酸糖转运体的结构基础。这些消息来源 NIGMS的资助使我的实验室能够回答有关糖运输和细胞处理的基本问题。 目前的建议体现了米拉资助计划的精神，使我能够解决更大的问题，这些问题包括 经常被称为“高风险”或“雄心勃勃的科学”，但这是每个科学家真正梦想的结果 正在获取。阐明膜转运蛋白的结构-功能关系特别危险，需要长时间的- 任期承诺和灵活性，以探索不同的研究和方法方向，并开发新的 接近了。Mira的稳定性和灵活性使我们能够做到这一点：尝试新的探索性 研究，这不仅将确定作为直接药物靶标的人类转运蛋白的结构，而且还 描述了它们的运输机制，这显然将适用于一般许多其他运输商。

PROJECT SUMMARY/ABSTRACT Sugars, in particular glucose, are bioenergetic molecules involved in a broad range of essential cellular processes. These metabolites, and their derivatives, are essential intermediates in glycolytic pathways leading to the production of ATP and are further used in the glycosylation of proteins and other macromolecules as part of the biosynthetic-secretory pathway. In humans, glucose is absorbed in the small intestine by enterocytes and delivered to the bloodstream. Blood glucose concentrations are tightly regulated by hormonal control and conserved reabsorption mechanisms in the kidneys. Secondary active transporters facilitate these absorption/reabsorption processes as well as the exclusive delivery of activated sugar molecules to the ER and Golgi. Disturbances in these functions are associated with numerous human disorders, such as type II diabetes. It is, therefore, a critical objective of biomedical research to understand the structural intricacies of these dynamic transporters. During my 15-year tenure as an independent investigator, my lab has produced a number of experimental firsts—the first crystal structure of a sodium glucose transporter, the first crystal structure of the Voltage Dependent Anion Channel, and the firsts to use these coordinates for their biochemical and biophysical characterization. The last five years have been extremely fruitful for my lab. We have complimented these original structures with new structures in distinct conformations and incorporated their biophysical characterization in effort to elucidate their transport mechanisms. These findings have direct implications to our collective understanding of associated diseases and aid in drug development. This has been made possible due to my long-standing R01 funded by NIGMS that is currently in its 14th year. Additionally, I was recently awarded a new R01 that aims to elucidate the structural basis of transport for Nucleotide Sugar Transporters. These sources of NIGMS funding have allowed my lab to answer fundamental questions regarding sugar transport and cellular processing. This current proposal embodies the spirit of the MIRA funding scheme by allowing me to tackle bigger questions that are frequently referred to as `Higher-Risk' or `Ambitious Science', but that are the results every scientist truly dreams of acquiring. Elucidating the structure-function relationship of membrane transporters is particularly risky and requires a long- term commitment and flexibility to explore different directions of research and methodologies and developing new approaches. The stability and flexibility incorporated into the MIRA allows us to do exactly that: try new exploratory research, which will not only determine structures of human transporters that are direct pharmaceutical targets, but also delineate their mechanism of transport that will clearly be applicable to many other transporters in general.