Unraveling the mammalian secretory pathway through systems biology and algorithm development

通过系统生物学和算法开发揭示哺乳动物的分泌途径

• 批准号: 10413925
• 负责人: Nathan Enoch Lewis
• 金额: $ 43.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413925
• 关键词: Algorithmic Software; Alzheimer' s Disease; Cell Adhesion Molecules; Cells; Code; Communicable Diseases; Communication; Communities; Computer Models; Disease; Environment; Enzymes; Extracellular Matrix; Genes; Genomics; Hormone Receptor; Hormone secretion; Human; Human Genome; Individual; Liver; Malignant Neoplasms; Mathematics; Membrane Proteins; Messenger RNA; Metabolic syndrome; Modeling; Molecular Diagnosis; Pathway interactions; Process; Production; Proteins; Research Personnel; Resources; Role; Signal Transduction; System; Systems Biology; Techniques; Tissues; Work; algorithm development; amyloid formation; base; cell type; computational platform; data resource; endoplasmic reticulum stress; experimental study; extracellular; receptor; software development; tool; trafficking

ABSTRACT The mammalian secretory pathway regulates a cell’s extracellular interactions by making most signals and receptors that moderate communication. Furthermore, it makes cell adhesion molecules and the extracellular matrix components. Indeed it makes most proteins needed for a cell to interact with its extracellular environment, which includes ~⅓ of their protein-coding genes in the human genome. The pathway has hundreds of machinery proteins used for synthesizing and trafficking secreted proteins, but each of these have their unique role in the process. However, for the ~8000 protein products of the secretory pathway, it remains unclear what machinery is needed for each one. To further complicate this, each tissue expresses its own subset of genes for the secretory pathway. Understanding the organization of the pathway and the interactions between the secretory pathway machinery and secreted protein products is of considerable importance since many diseases involve changes in the abundance of secreted and/or membrane proteins, and these are not always accompanied by changes in mRNA. That is, the secretory pathway itself is regulating changes in hormone secretion, managing ER stress, or amyloid formation. Thus, there is a fundamental need to understand (1) what the secretory pathway machinery does, (2) which secreted and membrane proteins rely upon it, (3) how the hundreds of machinery proteins work together, and (4) what regulates their functions. All of these items require systems-level experiments, tools, and analyses to fully understand. Here we are developing such resources for the community to answer fundamental questions. In this work, we are mapping out all of the secretory pathway machinery and detailing their functions. We describe their functions mathematically, and build computational models to account for their concerted functions, even for individual tissues and cell types. Furthermore we are developing software and algorithms to help analyze the models and use them to diagnose the molecular bases underlying secretory disorders. We are further developing and deploying experimental techniques to more fully identify all of the secretory machinery proteins needed to facilitate the production of each specific secreted or membrane protein, and will use those techniques to identify these interactions for liver-secreted proteins. Finally, we are using genomics and systems biology techniques to unravel the regulatory mechanisms controlling the tissue-specific expression of the secretory pathway. Through this, valuable resources will be developed and shared with the community to make it easier to study the secretory pathway as a biomolecular system.

摘要 哺乳动物的分泌途径通过产生大多数信号来调节细胞外的相互作用 以及调节交流的受体。此外，它还使细胞黏附分子和 细胞外基质成分。事实上，它制造了细胞与其相互作用所需的大部分蛋白质 细胞外环境，包括它们在人类基因组中编码蛋白质的基因的~⅓。这条路 有数百种用于合成和运输分泌蛋白质的机械蛋白质，但每一种 在这一过程中发挥着独特的作用。然而，对于分泌途径的~8000个蛋白质产物，它 目前还不清楚每一台都需要什么机械设备。更复杂的是，每个组织都表达了它的 拥有分泌途径的基因子集。了解路径的组织和 分泌途径机制和分泌的蛋白质产物之间的相互作用是相当重要的。 由于许多疾病涉及分泌和/或膜蛋白丰度的变化， 而这些并不总是伴随着信使核糖核酸的变化。也就是说，分泌途径本身是调节的。 激素分泌的变化，管理内质网压力，或淀粉样蛋白的形成。因此，有一个根本的需要。 为了了解(1)分泌途径机制的作用，(2)哪些分泌和膜蛋白依赖于 在此基础上，(3)成百上千的机械蛋白质如何协同工作，以及(4)是什么调节它们的功能。所有的 这些项目需要系统级的实验、工具和分析才能完全理解。我们到了 开发这些资源，供社会回答基本问题。在这项工作中，我们正在绘制 列出了所有的分泌途径机制，并详细说明了它们的功能。我们描述了它们的功能 从数学上讲，并建立计算模型来解释它们的协调功能，即使是对个人 组织和细胞类型。此外，我们正在开发软件和算法来帮助分析模型和 使用它们来诊断潜在的分泌障碍的分子基础。我们正在进一步发展和 利用实验技术更全面地鉴定所有需要的分泌机械蛋白 促进每一种特定分泌或膜蛋白的生产，并将利用这些技术 确定肝脏分泌蛋白的这些相互作用。最后，我们正在使用基因组学和系统生物学 解开控制分泌物组织特异性表达的调节机制的技术 路径。通过这一点，宝贵的资源将被开发并与社区共享，使其更容易 将分泌途径作为生物分子系统进行研究。