Cell Biology of Nucleoside Transporters

我的研究项目（自1998年以来由NSERC资助）研究转运蛋白，这是一类蛋白质，正如它们的名字所暗示的那样，将分子和化合物运送到细胞或细胞内的隔间。细胞就像工厂一样，全年无休地运转。 他们不断地接受供应，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，细胞需要有一定的供应品运送到细胞中，以支持某些类型的工作。细胞还需要运送出细胞内产生的产物并处理废物。包围每个细胞的细胞膜是细胞内所需的许多分子的屏障。所以细胞膜包含了位于细胞膜上的门户或通道，使某些分子或化合物能够进出细胞。这些转运蛋白，被称为转运蛋白，根据它们转运的分子或化合物的特定类别或组而具有不同的“风味”。例如，能量分子葡萄糖通过葡萄糖转运蛋白转运到细胞中。 我们研究核苷转运蛋白（NT），它转运一类被称为核苷的分子。细胞需要核苷来制造DNA和其他在细胞信号传导和能量管理中很重要的细胞元件。嘌呤核苷，腺苷，也可以通过NT释放到细胞外，然后与其他细胞表面上发现的特殊腺苷受体相互作用。细胞腺苷信号传导在许多生理情况下是重要的，特别是在大脑和心脏中，特别是在压力或低氧水平期间。NT也是用于抗癌、抗病毒和抗寄生虫治疗的一大类药物的进入途径。了解NTs如何工作以及如何调节它们在临床上很重要。 NTs在大约15年前在分子水平上被鉴定（克隆），但已被证明是具有挑战性的生物化学研究（通常是膜蛋白的情况）。 我们对它们的三维结构知之甚少，对它们如何运输核苷也几乎一无所知。 然而，在过去的15年中，我们已经确定了NTs在腺苷信号传导和细胞生理学中的重要作用。 最近，我们确定并表征了一种NT在调节细胞增殖中的意想不到的作用，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。在此之前的工作的基础上，我们使用各种生物化学和分子技术来研究NT的结构，功能，调节和贡献的健康日常生活的忙碌细胞。

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.