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
基本信息
- 批准号:10207258
- 负责人:
- 金额:$ 46.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Algorithmic SoftwareAlzheimer&aposs DiseaseCell Adhesion MoleculesCellsCodeCommunicable DiseasesCommunicationCommunitiesComputer ModelsDiseaseEnvironmentEnzymesExtracellular MatrixGenesGenomicsHormone ReceptorHormone secretionHumanHuman GenomeIndividualLiverMalignant NeoplasmsMathematicsMembrane ProteinsMessenger RNAMetabolic syndromeModelingMolecular DiagnosisPathway interactionsProcessProductionProteinsResearch PersonnelResourcesRoleSignal TransductionSystemSystems BiologyTechniquesTissuesWorkalgorithm developmentamyloid formationbasecell typecomputational platformdata resourceendoplasmic reticulum stressexperimental studyextracellularreceptorsoftware developmenttooltrafficking
项目摘要
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制造大多数信号来调节细胞的细胞外相互作用
和调节交流的受体。此外,它使细胞粘附分子和
细胞外基质成分。事实上,它制造了细胞与其细胞相互作用所需的大多数蛋白质。
细胞外环境,其中包括人类基因组中蛋白质编码基因的伪基因。该途径
有数以百计的机器蛋白用于合成和运输分泌蛋白,但每一个这些
在这一过程中发挥着独特的作用。然而,对于分泌途径的约8000种蛋白质产物,
目前尚不清楚每一项需要何种机制。为了进一步复杂化,每个组织表达其
自己的分泌途径的基因子集。理解路径的组织和
分泌途径机械和分泌的蛋白质产物之间的相互作用是相当重要的
重要性由于许多疾病涉及分泌和/或膜蛋白丰度的变化,
这些变化并不总是伴随着mRNA的变化。也就是说,分泌途径本身
激素分泌的变化,管理ER应激或淀粉样蛋白形成。因此,有一个基本的需要,
了解(1)分泌途径机制的作用,(2)哪些分泌蛋白和膜蛋白依赖于
(3)数百种机器蛋白如何协同工作,(4)是什么调节它们的功能。所有
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
为社区开发这些资源,以回答基本问题。在这项工作中,我们正在绘制
所有的分泌途径机制,并详细说明其功能。我们描述了它们的功能
数学上,并建立计算模型来解释它们的协调功能,即使是对个人来说,
组织和细胞类型。此外,我们正在开发软件和算法,以帮助分析模型,
用它们来诊断分泌失调的分子基础。我们正在进一步发展,
部署实验技术,以更充分地确定所有的分泌机制所需的蛋白质,
促进每种特定分泌蛋白或膜蛋白的产生,并将使用这些技术来
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
技术,以解开控制的组织特异性表达的分泌的调节机制,
通路通过这一点,有价值的资源将被开发并与社区共享,使其更容易
将分泌途径作为一个生物分子系统来研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nathan Enoch Lewis其他文献
Nathan Enoch Lewis的其他文献
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{{ truncateString('Nathan Enoch Lewis', 18)}}的其他基金
Glycoengineering of CHO cells to express recombinant alpha-1 antitrypsin
CHO细胞的糖工程表达重组α-1抗胰蛋白酶
- 批准号:
10484110 - 财政年份:2022
- 资助金额:
$ 46.1万 - 项目类别:
ImmCellFIE: producing high-resolution snapshots of the functions of immune cells
ImmCellFIE:生成免疫细胞功能的高分辨率快照
- 批准号:
10199979 - 财政年份:2020
- 资助金额:
$ 46.1万 - 项目类别:
ImmCellFIE: producing high-resolution snapshots of the functions of immune cells
ImmCellFIE:生成免疫细胞功能的高分辨率快照
- 批准号:
10027185 - 财政年份:2020
- 资助金额:
$ 46.1万 - 项目类别:
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:
10826657 - 财政年份:2016
- 资助金额:
$ 46.1万 - 项目类别:
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 - 财政年份:2016
- 资助金额:
$ 46.1万 - 项目类别:
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:
10654737 - 财政年份:2016
- 资助金额:
$ 46.1万 - 项目类别:
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:
9142975 - 财政年份:2016
- 资助金额:
$ 46.1万 - 项目类别: