Oxysterol Regulation of Microbial Pathogenesis

氧甾醇对微生物发病机制的调节

基本信息

  • 批准号:
    10592354
  • 负责人:
  • 金额:
    $ 57.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary The proposed project focuses on our recent discovery that immunological production of the oxysterol 25- Hydroxycholesterol (25HC) potently inhibits the cellular dissemination of two globally important bacterial pathogens, Listeria monocytogenes and Shigella flexneri. The anti-bacterial activity of 25HC is mediated through mobilization of the accessible cholesterol pool from the plasma membrane (PM). Accessible cholesterol is one of three pools into which PM cholesterol is sub-divided and this pool regulates cellular signaling pathways that control lipid homeostasis and cell growth. By first characterizing the molecular mechanism by which 25HC induces internalization of accessible cholesterol (Aim 1), these studies will reveal how cholesterol can be rapidly transported in response to cytokine stimulation. Second, we will determine how remodeling of PM cholesterol suppresses Listeria and Shigella from penetrating the cell-to-cell contact junctions of the mucosal epithelium (Aim 2). This work will reveal how mammals enhance the barrier function of mucosal surfaces through cholesterol metabolic pathways and will identify points of weakness in the mucosal immune system that may be exploited by numerous microbial pathogens. Third, we will develop new technologies for monitoring cholesterol dynamics in the living organism and use these technologies to determine the tissues and cell types that mobilize accessible cholesterol in response to bacterial infection (Aim 3). Finally, the physiological significance of oxysterol-mediated immune pathways will be investigated in mammalian model organisms using three complementary mouse models that disrupt 25HC activation, production, and downstream activity (Aim 4). Insights gleaned from these studies, which range from basic biochemistry to mouse models of infection, will explain how the human immune system has adapted fundamental aspects of cholesterol metabolism to protect barrier cells from intracellular bacterial infection. Developing new drugs that mimic the molecular activity of 25HC as determined in this proposal would be an innovative approach to combat human infectious disease associated with pathogens that exploit host cholesterol metabolism. These studies will also provide new insights into the pathogenic mechanisms of an important infectious disease-causing agent and also into the biology of the human inflammatory response.
项目总结

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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Neal Mathew Alto其他文献

<em>Shigella</em> Puts the Brakes on the Host Cell Cycle
  • DOI:
    10.1016/j.chom.2007.08.003
  • 发表时间:
    2007-09-13
  • 期刊:
  • 影响因子:
  • 作者:
    Neal Mathew Alto
  • 通讯作者:
    Neal Mathew Alto

Neal Mathew Alto的其他文献

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{{ truncateString('Neal Mathew Alto', 18)}}的其他基金

Oxysterol Regulation of Microbial Pathogenesis
氧甾醇对微生物发病机制的调节
  • 批准号:
    10381602
  • 财政年份:
    2021
  • 资助金额:
    $ 57.36万
  • 项目类别:
Oxysterol Regulation of Microbial Pathogenesis
氧甾醇对微生物发病机制的调节
  • 批准号:
    10178988
  • 财政年份:
    2021
  • 资助金额:
    $ 57.36万
  • 项目类别:
Resolution of Inflammation by the SIX-family Transcription Factors
通过六家族转录因子解决炎症
  • 批准号:
    10328259
  • 财政年份:
    2020
  • 资助金额:
    $ 57.36万
  • 项目类别:
Resolution of Inflammation by the SIX-family Transcription Factors
通过六家族转录因子解决炎症
  • 批准号:
    10112827
  • 财政年份:
    2020
  • 资助金额:
    $ 57.36万
  • 项目类别:
Resolution of Inflammation by the SIX-family Transcription Factors
通过六家族转录因子解决炎症
  • 批准号:
    10553188
  • 财政年份:
    2020
  • 资助金额:
    $ 57.36万
  • 项目类别:
Bacterial Regulation of Eukaryotic Signaling Enzymes: Structure and Function
真核信号酶的细菌调节:结构和功能
  • 批准号:
    8235694
  • 财政年份:
    2012
  • 资助金额:
    $ 57.36万
  • 项目类别:
Bacterial Regulation of Eukaryotic Signaling Enzymes: Structure and Function
真核信号酶的细菌调节:结构和功能
  • 批准号:
    8788709
  • 财政年份:
    2012
  • 资助金额:
    $ 57.36万
  • 项目类别:
Bacterial Regulation of Eukaryotic Signaling Enzymes: Structure and Function
真核信号酶的细菌调节:结构和功能
  • 批准号:
    8415960
  • 财政年份:
    2012
  • 资助金额:
    $ 57.36万
  • 项目类别:
Bacterial Regulation of Eukaryotic Signaling Enzymes: Structure and Function
真核信号酶的细菌调节:结构和功能
  • 批准号:
    8603244
  • 财政年份:
    2012
  • 资助金额:
    $ 57.36万
  • 项目类别:
Type III effector regulation of host GTPase signaling
宿主 GTPase 信号转导的 III 型效应器调节
  • 批准号:
    8503581
  • 财政年份:
    2009
  • 资助金额:
    $ 57.36万
  • 项目类别:

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