Mechanism and function of organization of secretory cargo export from the endoplasmic reticulum.

自从细胞显微镜出现以来，哺乳动物细胞的内部组织已经有了很好的记录。因此，令人惊讶的是，我们对细胞为什么会这样布局知之甚少--简单地说，形式如何决定功能？一个很好的例子来自分泌途径的组织。所有从你的细胞分泌的蛋白质都经过这条途径-所有激素（胰岛素，生长因子，消化酶），所有神经递质，所有由你的免疫细胞产生的抗体。此外，位于细胞表面的所有蛋白质都是通过分泌途径来识别这些关键信号分子的。事实上，所有内部细胞膜都由蛋白质组成，这些蛋白质通过分泌途径靶向这些单独的隔室，并用于确定它们所在的膜的身份。那么，为什么分泌途径的第一步是在称为过渡性ER（tER）的离散位点组织的呢？当用特异性标记物标记时，可以在细胞中看到的这些点是分泌途径空间组织的第一个位点。因此，就像地基定义建筑物的架构一样，这些位置定义了单元的架构。我们和我们的新合作者已经确定了两种定义这些tER位点的蛋白质，现在希望继续展示这些蛋白质如何共同作用以产生这些位点，以及它们相互依赖的功能如何与tER的核心组织相关。根据我们的一些初步数据，我们现在可以问一个基本问题，即组织如何指导功能。我们有证据表明，我们可以在不阻碍核心活动的情况下破坏组织。我们建议研究该组织在分泌途径的核心活动中的作用，特别是关注tER组织在体内最丰富的蛋白质胶原蛋白分泌中的作用。我们有很好的证据表明，这些核心蛋白在这里发挥着关键作用，一些证据表明，它们甚至可能直接参与胶原蛋白合成过程中的加工。资助这个项目将使我们能够为我们对细胞组织和功能的基本理解做出重大贡献。这些发现对于那些寻求研究疾病中该途径的功能障碍的人以及那些寻求操纵它以获得治疗益处（产生临床活性分泌分子，改变细胞的分泌负荷等）的人具有良好的相关性。

The internal organization of mammalian cells has been well documented since the dawn of cellular microscopy. It is therefore quite astonishing how little we know about why the cell is laid out in this way - in simple terms, how does form dictate function? A great example of this comes from the organization of the secretory pathway. All proteins secreted from your cells go through this pathway - all hormones (insulin, growth factors, digestive enzymes), all neurotransmitters, all antibodies made by your immune cells. Furthermore, all of the proteins that sit on the surface of your cells to recognize these key signalling molecules are put there by the secretory pathway. Indeed, all internal cell membranes are composed of proteins that are targeted to these individual compartments by the secretory pathway and serve to define the identity of the membranes where they reside. Why then is the first step of the secretory pathway organized at discrete sites known as transitional ER (tER). These spots that can be seen in the cell when labelled with specific markers are the first site of spatial organization of the secretory pathway. As such, in the same way that the foundations define the architecture of a building, these sites define the architecture of the cell. We and our new collaborators have identified two of the proteins that define these tER sites and now wish to go on to show how these act together to generate these sites and how their interdependent function relates to the core organization of the tER. Following on from some of our preliminary data, we are now in a position to ask the fundamental question of how tER organization directs function. We have evidence that we can disrupt organization without blocking core activity. We propose to investigate the role of this organization in the core activities of the secretory pathway and in particular focus on the role of tER organization in the secretion of the most abundant protein in your body, collagen. We have good evidence that these core proteins play a key role here and some evidence that they might even be involved directly in processing collagen during its synthesis. Funding this project will enable us to make major contributions to our fundamental understanding of cellular organization and function. Such findings have good potential for relevance to those seeking to study the dysfunction of this pathway in disease as well as those seeking to manipulate it for therapeutic benefit (the production of clinically active secreted molecules, modifying the secretory load of cells etc).