Cell Biology of Nucleoside Transporters

核苷转运蛋白的细胞生物学

• 批准号: RGPIN-2017-05193
• 负责人: Coe, Imogen
• 金额: $ 3.64万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=689842
• 关键词: Cell; Biology; Nucleoside; Transporters

My research program (funded by NSERC since 1998) studies transporters, which are a class of proteins, that, as their name suggests, transport molecules and compounds into and out of cells or compartments within cells. Cells are like factories that are running 24/7 all year round. They are continually receiving supplies, making and delivering different products for different purposes and producing waste. Like factories, cells need to have certain supplies shipped into the cell, to support the certain types of work. Cells also need to ship out the products that have been generated within the cell and deal with waste. The cell membrane that surrounds every cell is a barrier to many molecules that are needed inside the cell. So cell membranes contain portals or gateways that sit in the cell membrane and enable the movement of certain molecules or compounds into and/or out of the cells. These transport proteins, known as transporters, come in different "flavours" depending on the particular class or group of molecules or compounds they transport. For instance, the energy molecule glucose is transported into cells by glucose transporters. We work on nucleoside transporters (NTs), which transport a class of molecules known as nucleosides. Nucleosides are needed by cells to make DNA and other cellular elements that are important in cell signaling and energy management. The purine nucleoside, adenosine, can also be released by NTs to the outside of the cell where it then interacts with special adenosine receptors found on the surface of other cells. Cellular adenosine signaling is important in many physiological situations, especially in the brain and heart, particularly during stress or low oxygen levels. NTs are also the route of entry for a large class of drugs used in anti-cancer, anti-viral and anti-parasite treatments. Understanding how NTs work and how they are regulated is important clinically. ******NTs were identified (cloned) at the molecular level about 15 years ago but have proved to be challenging to study biochemically (as is often the case with membrane proteins). We know little about what they look like (in terms of their three-dimensional structure) and almost nothing about how they actually transport nucleosides. However, over the last 15+ years, we have identified the important roles NTs play in adenosine signaling and cell physiology. Recently, we identified and characterized an unexpected role of one type of NT in regulating the proliferation of cells, which was an unexpected but very exciting finding, shedding new light on how cells manage the complex task of manufacturing the huge amounts of DNA needed for repeated cellular division. Building on this previous work, we use a variety of biochemical and molecular techniques to study the structure, function, regulation and contributions of NTs to the healthy everyday lives of busy cells.

我的研究项目(自1998年以来由NSERC资助)研究的是转运蛋白，顾名思义，转运蛋白是一类蛋白质，它将分子和化合物运入和运出细胞或细胞内的隔间。电池就像一家全年24小时运转的工厂。他们不断地接收物资，为不同的目的制造和交付不同的产品，并产生废物。像工厂一样，电池需要将某些补给运到电池中，以支持某些类型的工作。电池还需要将电池内产生的产品运出，并处理废物。包围着每个细胞的细胞膜是细胞内需要的许多分子的屏障。因此，细胞膜包含位于细胞膜中的入口或门户，使某些分子或化合物能够进入和/或离开细胞。这些转运蛋白被称为转运蛋白，根据它们运输的分子或化合物的特定类别或组，它们有不同的“味道”。例如，能量分子葡萄糖通过葡萄糖转运蛋白运输到细胞内。我们致力于核苷转运体(NTS)的研究，它可以运输一类被称为核苷的分子。细胞需要核苷来制造DNA和其他细胞元素，这些元素在细胞信号和能量管理中非常重要。嘌呤核苷，腺苷，也可以被NTS释放到细胞外，在那里它与其他细胞表面发现的特殊腺苷受体相互作用。细胞腺苷信号在许多生理情况下很重要，特别是在大脑和心脏，特别是在应激或低氧水平时。NTS也是一大类用于抗癌、抗病毒和抗寄生虫治疗的药物的进入途径。了解NTS是如何工作的，以及它们是如何被调控的，这在临床上很重要。*NTs在大约15年前在分子水平上被鉴定(克隆)，但已被证明对生物化学研究具有挑战性(膜蛋白通常是这种情况)。我们对它们的外观(就其三维结构而言)知之甚少，对它们实际如何运输核苷几乎一无所知。然而，在过去的15年里，我们已经确定了NTS在腺苷信号转导和细胞生理学中扮演的重要角色。最近，我们发现并表征了一种类型的NT在调节细胞增殖方面的意想不到的作用，这是一个意想不到但非常令人兴奋的发现，为细胞如何管理制造重复细胞分裂所需的大量DNA的复杂任务提供了新的线索。在之前工作的基础上，我们使用各种生化和分子技术来研究NTS的结构、功能、调节以及对繁忙细胞健康日常生活的贡献。