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

破译细胞糖转运的分子细节及其在疾病中的作用

• 批准号: 10077573
• 负责人: Jeffrey S Abramson
• 金额: $ 72.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077573
• 关键词: Award; Biochemical; Bioenergetics; Biomedical Research; Blood Circulation; Blood Glucose; Cell physiology; Complement; Crystallization; Disease; Dreams; Enterocytes; Funding; Glucose; Glucose Transporter; Golgi Apparatus; Hormonal; Human; Infection; Kidney; Medical; Membrane Transport Proteins; Metabolism; Molecular; Molecular Conformation; National Institute of General Medical Sciences; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmacologic Substance; Process; Production; Protein Glycosylation; Research; Research Methodology; Research Personnel; Roentgen Rays; Role; Scheme; Science; Scientist; Small Intestines; Sodium; Source; Spectrum Analysis; Structure; Structure-Activity Relationship; Voltage-Dependent Anion Channel; absorption; biophysical properties; drug development; flexibility; high risk; interest; macromolecule; microbial; molecular dynamics; novel strategies; sugar; sugar nucleotide

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.

项目概要/摘要 糖，特别是葡萄糖，是参与多种重要细胞过程的生物能分子。这些 代谢物及其衍生物是糖酵解途径中必需的中间体，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，葡萄糖在小肠中被肠细胞吸收并输送到血液中。血糖 浓度受到激素控制和肾脏中保守的重吸收机制的严格调节。中学 主动转运蛋白促进这些吸收/再吸收过程以及活性糖的专门输送 分子到内质网和高尔基体。这些功能的紊乱与许多人类疾病有关，例如类型 二、糖尿病。因此，理解这些动态的结构复杂性是生物医学研究的一个关键目标。 运输者。 在我作为独立研究者的 15 年任期中，我的实验室创造了许多实验第一——第一个 钠葡萄糖转运蛋白的晶体结构，电压依赖性阴离子通道的第一个晶体结构， 并首次使用这些坐标进行生化和生物物理表征。过去五年已 对我的实验室来说非常富有成效。我们用不同构象的新结构来补充这些原始结构 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药物开发援助产生直接影响。这个已经做了 这可能是因为我长期由 NIGMS 资助的 R01 目前已经是第 14 个年头了。另外，我最近 授予新的 R01，旨在阐明核苷酸糖转运蛋白的运输结构基础。这些来源 NIGMS 的资金使我的实验室能够回答有关糖转运和细胞处理的基本问题。 当前的提案体现了 MIRA 资助计划的精神，让我能够解决以下更大的问题： 通常被称为“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 获取。阐明膜转运蛋白的结构与功能关系尤其危险，需要长期研究 任期承诺和灵活性，探索不同的研究方向和方法并开发新的 接近。 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 研究不仅将确定作为直接药物靶点的人类转运蛋白的结构，而且还将确定 描述其运输机制，该机制显然适用于许多其他运输者。