ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
基本信息
- 批准号:10299123
- 负责人:
- 金额:$ 39.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAcuteAreaAutophagocytosisAutophagosomeBiogenesisBiologyBiomedical EngineeringCell DeathCell divisionCellsCellular MembraneChemicalsComplexCytokinesisCytoplasmDiseaseEndosomesEpithelial CellsEstersExcisionFaceFundingGrantHIV BuddingHealthHomeostasisImageInflammasomeInflammationInflammatory ResponseInvadedKineticsLeucineLipid PeroxidationLysosomesMediatingMembraneMembrane ProteinsMetabolicModelingMolecularNeckNecrosisNuclear EnvelopeOrganellesParticulatePathway interactionsPhagocytesPhagosomesPlayProcessProteinsResolutionRoleSilicon DioxideSorting - Cell MovementSterilityStressSystemTestingThinkingVesicleViralWorkYeastscytokineendosome membraneextracellularinsightnanoscalepathogenperoxisomeprotein degradationrecruitrepairedresponsesealtraffickingvesicular release
项目摘要
The endolysosomal network is the portal by which extracellular material enters the cell. As such, the
membranes of the endosomes, phagosomes, and lysosomes that comprise this network face challenges from
pathogens and other internalized materials as well as from metabolic and chemical stresses. Consequences of
damage vary according to the specific compartment and degree of damage, but extensive lysosomal
membrane permeabilization triggers cell death while limited disruption of endosomes and phagosomes by
particulate material and pathogens leads to inflammasome activation and ensuing cytokine responses. A
widely deployed strategy for removing damaged organelles involves the use of selective autophagy, referred to
as lysophagy. Removal is, however, unnecessary if organelles are instead repaired. We recently discovered a
new role for the ESCRT (endosomal sorting complex required for transport) machinery in responding to nano-
scale disruptions in endolysosomal membranes and promoting their repair. In this proposal, we will build on
this discovery and test the hypothesis that ESCRTs (and in particular ESCRT-III proteins) act as a dynamic
membrane stabilizing system to protect vulnerable membranes across the endolysosomal network and
beyond. Two aims will exploit and explore responses to two experimentally tractable and sterile endolysosomal
disruptants that potently engage the ESCRT machinery. In Aim 1, we will determine how the ESCRT
machinery recognizes and counteracts lysosomal membrane stress induced by L-leucyl-L-leucine methyl ester
(LLOMe). This will involve characterizing the membrane stress responsible for engaging ESCRTs, defining the
molecular pathway(s) involved and identifying “keystone” ESCRT-III proteins, delineating the molecular
features required for repair, and identifying pathways that trigger this stabilizing response. In Aim 2, we will
examine how ESCRTs respond to and repair silica induced membrane damage in epithelial and phagocytic
cells. This will include testing a role for Fe2+-dependent lipid peroxidation in engaging ESCRTs, imaging the
relative role and dynamics of ESCRT components on phagosomal membranes, and testing the hypothesis that
ESCRTs limit endolysosomal damage in phagocytic cells and thereby dampen inflammation associated with
the many things that transit through these pathways. The insights gained from this work will be applicable to
understanding how ESCRTs sense and respond to a broad range of membrane stresses.
内溶酶体网络是细胞外物质进入细胞的门户。因此,
构成该网络的内体、吞噬体和溶酶体的膜面临着来自以下方面的挑战:
病原体和其他内化物质以及代谢和化学应激。的后果
损害根据具体的隔室和损害程度而有所不同,但广泛的溶酶体
膜透化作用引发细胞死亡,同时有限地破坏内体和吞噬体
颗粒物质和病原体导致炎症小体激活和随后的细胞因子反应。一个
广泛采用的去除受损细胞器的策略涉及使用选择性自噬,称为
如溶食症。然而,如果细胞器被修复,则无需去除。我们最近发现了一个
ESCRT(运输所需的内体分选复合物)机器在响应纳米-
规模破坏内溶酶体膜并促进其修复。在本提案中,我们将建立在
这一发现并检验了 ESCRT(特别是 ESCRT-III 蛋白)作为动态蛋白的假设
膜稳定系统,保护内溶酶体网络中脆弱的膜,
超过。两个目标将利用和探索对两种实验上易处理且无菌的内溶酶体的反应
有效参与 ESRT 机制的干扰物。在目标 1 中,我们将确定 ESRT 如何
机器识别并抵消 L-亮氨酰-L-亮氨酸甲酯诱导的溶酶体膜应激
(洛梅)。这将涉及表征负责参与 ESRT 的膜应力,定义
涉及并识别“关键”ESCRT-III 蛋白的分子途径,描绘了分子
修复所需的功能,并确定触发这种稳定反应的途径。在目标 2 中,我们将
检查 ESCRT 如何响应和修复二氧化硅诱导的上皮细胞和吞噬细胞膜损伤
细胞。这将包括测试 Fe2+ 依赖性脂质过氧化在参与 ESRT 中的作用,对
ESCRT 成分在吞噬体膜上的相对作用和动态,并检验以下假设:
ESCRT 限制吞噬细胞的内溶酶体损伤,从而抑制与吞噬细胞相关的炎症
通过这些路径传递的许多事物。从这项工作中获得的见解将适用于
了解 ESRT 如何感知和响应广泛的膜应力。
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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Phyllis I Hanson其他文献
Phyllis I Hanson的其他文献
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{{ truncateString('Phyllis I Hanson', 18)}}的其他基金
ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
- 批准号:
10447626 - 财政年份:2017
- 资助金额:
$ 39.59万 - 项目类别:
ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
- 批准号:
10798848 - 财政年份:2017
- 资助金额:
$ 39.59万 - 项目类别:
ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
- 批准号:
10676296 - 财政年份:2017
- 资助金额:
$ 39.59万 - 项目类别:
ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
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10683489 - 财政年份:2017
- 资助金额:
$ 39.59万 - 项目类别:
Tracking Intracellular Pathways to Abeta Generation
追踪 Abeta 生成的细胞内途径
- 批准号:
9264170 - 财政年份:2017
- 资助金额:
$ 39.59万 - 项目类别:
ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING
内溶酶体转运中 ESCRT 功能的分析
- 批准号:
9264291 - 财政年份:2017
- 资助金额:
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NANOSCALE ARCHITECTURE OF ESCRT MACHINERY IN HIV RELEASE
HIV 释放中 ESCRT 机器的纳米级架构
- 批准号:
8993494 - 财政年份:2015
- 资助金额:
$ 39.59万 - 项目类别:
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