INTEGRATED MODELING OF PROTEIN AND MEMBRANE TRAFFIC IN THE SECRETORY PATHWAY

描述（由申请人提供）：在人类细胞中，所有膜蛋白（包括许多（如果不是大多数）药物靶点）和所有肽和蛋白质激素（包括胰岛素和瘦素）都通过内膜系统从细胞中产生它们的地方到达它们发挥作用的地方。被认为与内膜系统有关的疾病包括阿尔茨海默氏痴呆症、囊性纤维化和几种脂肪和胆固醇代谢疾病。内膜系统本身由3个主要部分组成：内质网（ER），高尔基体和质膜，加上一系列复杂的内化和再循环途径，归类为内吞作用。这项研究的长期目标是建立一个分泌途径和内吞系统的计算机模型，该模型已成功地与实验结果进行了对比，并可用于做出新的预测。我们的短期目标是测试胆固醇在控制内膜系统中的可能作用。通过将荧光蛋白和胆固醇的活细胞成像与系统生物学和动力学建模相结合，我们将测试胆固醇驱动的膜分配是内膜系统的组织原理的假设。重点将在四个特定领域测试这一想法：1）胆固醇调节蛋白质从内质网输出，2）确定高尔基体或脂质转运蛋白是否将胆固醇从ER携带到质膜，3）高尔基体中胆固醇驱动的分配，以及4）内吞作用中的胆固醇运输途径。由于目标是这些重要细胞过程的综合模型，因此该模型还将根据世界各地其他实验室的关键实验结果进行测试。

DESCRIPTION (provided by applicant): In human cells, all membrane proteins (which include many if not most drug targets) and all peptide and protein hormones (including insulin and leptin) travel through the endomembrane system from the place where they are made in the cell to the place where they do their work. Diseases thought to involve the endomembrane system include Alzheimer's dementia, cystic fibrosis, and several diseases of fat and cholesterol metabolism. The endomembrane system itself consists of 3 major parts: the endoplasmic reticulum (ER), the Golgi apparatus and the plasma membrane, plus a complex series of internalization and recycling pathways grouped under the general heading of endocytosis. The long term goal of this research is to build a computer model of the secretory pathway and the endocytosis system that has been successfully tested against experimental results, and can be used to make new predictions. Our short-term goal is to test the possible roles of cholesterol in controlling the endomembrane system. By combining the live-cell imaging of fluorescent proteins and cholesterol with systems biology and kinetic modeling we will test the hypothesis that cholesterol-driven membrane partitioning is the organizing principle of the endomembrane system. The focus will be on testing this idea in four specific areas: 1) cholesterol-regulation of protein export from the endoplasmic reticulum, 2) determining whether the Golgi apparatus or lipid transfer proteins carry cholesterol from the ER to the plasma membrane, 3) cholesterol driven partitioning in the Golgi apparatus, and 4) cholesterol trafficking pathways in endocytosis. Because the goal is an integrated model of these important cell processes, the model will also be tested against key experimental results from other laboratories world-wide.