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

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,

项目成果

期刊论文数量(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

Signal relay during directed cell migration
定向细胞迁移过程中的信号中继
  • 批准号:
    10214472
  • 财政年份:
    2020
  • 资助金额:
    $ 39.59万
  • 项目类别:
Signal relay during directed cell migration
定向细胞迁移过程中的信号中继
  • 批准号:
    10655335
  • 财政年份:
    2020
  • 资助金额:
    $ 39.59万
  • 项目类别:
Signal relay during directed cell migration
定向细胞迁移过程中的信号中继
  • 批准号:
    10436900
  • 财政年份:
    2020
  • 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:
    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
  • 批准号:
    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:
    $ 39.59万
  • 项目类别:
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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