Dissecting the mechanism of RIPK1 kinase-dependent cell death in control of Yersinia infection

剖析 RIPK1 激酶依赖性细胞死亡控制耶尔森菌感染的机制

基本信息

  • 批准号:
    9285729
  • 负责人:
  • 金额:
    $ 20.86万
  • 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:
    2016-06-06 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary Immune defense against bacterial infection requires activation of conserved signaling pathways that upregulate production of inflammatory mediators to clear infection. Many pathogens, including the pathogenic Yersinia inhibit these signaling pathways in order to evade host immune defenses. Yersinia injects a virulence factor, YopJ, which blocks NF-ΚB and MAPK signaling. How immune defense is mediated against pathogens that block immune signaling pathways remains poorly understood. NF-κB blockade in macrophages exposed to bacterial PAMPs leads to cell death with characteristics of apoptosis, yet this death has pro-inflammatory consequences. Notably, increasing cytotoxicity of Y. pseudotuberculosis or Y. pestis results in decreased bacterial virulence, suggesting that induction of cell death in response to Yersinia serves as a host immune protective mechanism. Our central hypothesis is that cell death triggered in response to Yersinia blockade of NF-κB and MAPK releases pro-inflammatory signals that alert uninfected neighboring cells to the presence of infection. However, the cellular and molecular basis for this response remains unclear. Our recently published and preliminary data demonstrate that RIPK1 kinase activity is required for Yersinia-induced cell death. Moreover, RIPK1 kinase activity contributes to control of Yersinia infection and to inflammatory cytokine production in vivo. Nevertheless, how RIPK1 kinase activity and cell death are coupled to inflammatory responses and host defense against bacterial infection is not known. This is an important problem as this pathway likely responds to many pathogens that block critical innate immune signaling pathways and in the context of pathological stimuli that lead to RIPK1-induced cell death. We propose two Specific Aims to address this important gap in our knowledge. First we will define the cellular population that requires RIPK1 kinase activity, and determine whether RIPK1 functions in a cell-intrinsic or extrinsic manner to mediate anti-bacterial immune defense. Second, we will will determine the contribution of RIPK1 to downstream pathogen-specific immune responses and will dissect whether RIPK1 functions to control bacterial dissemination or replication.
项目摘要 针对细菌感染的免疫防御需要激活保守的信号通路, 产生炎症介质以清除感染。许多病原体,包括致病性耶尔森氏菌 抑制这些信号通路以逃避宿主的免疫防御。耶尔森氏菌注入一种毒力因子, YopJ,其阻断NF-ΚB B和MAPK信号传导。免疫防御是如何介导的, 阻断免疫信号通路仍然知之甚少。巨噬细胞NF-κB的阻断作用 细菌PAMPs导致具有凋亡特征的细胞死亡,但这种死亡具有促炎性, 后果显著增加Y. pseudotuberculosis或Y.鼠疫导致 细菌的毒力,表明诱导细胞死亡的反应耶尔森菌作为宿主免疫 保护机制我们的中心假设是,细胞死亡是由耶尔森氏菌对细胞的阻断引起的。 NF-κB和MAPK释放促炎信号,警告未感染的邻近细胞存在 感染然而,这种反应的细胞和分子基础仍不清楚。我们最近出版的 初步数据表明,RIPK 1激酶活性是耶尔森氏菌诱导的细胞死亡所必需的。 此外,RIPK 1激酶活性有助于控制耶尔森氏菌感染和炎性细胞因子 体内生产。然而,RIPK 1激酶活性和细胞死亡如何与炎症反应相关, 对细菌感染的反应和宿主防御尚不清楚。这是一个重要的问题, 途径可能对许多阻断关键先天免疫信号传导途径的病原体做出反应, 导致RIPK 1诱导的细胞死亡的病理刺激的背景。我们提出两个具体目标,以解决 这是我们知识中的一个重要缺口。首先,我们将确定需要RIPK 1激酶的细胞群体 活性,并确定RIPK 1是否以细胞内源性或外源性方式介导抗细菌 免疫防御其次,我们将确定RIPK 1对下游病原体特异性免疫应答的贡献。 免疫反应,并将剖析是否RIPK 1的功能,以控制细菌传播或复制。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

IGOR E BRODSKY其他文献

IGOR E BRODSKY的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('IGOR E BRODSKY', 18)}}的其他基金

Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
  • 批准号:
    10452195
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
  • 批准号:
    10580079
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
  • 批准号:
    10329911
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10435528
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
  • 批准号:
    10092916
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10200805
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10649640
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
  • 批准号:
    10557104
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Lymphothrombosis in gut health and disease
肠道健康和疾病中的淋巴血栓形成
  • 批准号:
    10018488
  • 财政年份:
    2019
  • 资助金额:
    $ 20.86万
  • 项目类别:
Defining the non-apoptotic role of Caspase-8 activity in anti-bacterial immune defense
定义 Caspase-8 活性在抗菌免疫防御中的非凋亡作用
  • 批准号:
    9229681
  • 财政年份:
    2017
  • 资助金额:
    $ 20.86万
  • 项目类别:

相似海外基金

The Role of Arginine Transport on Pancreatic Alpha Cell Proliferation and Function
精氨酸转运对胰腺α细胞增殖和功能的作用
  • 批准号:
    10678248
  • 财政年份:
    2023
  • 资助金额:
    $ 20.86万
  • 项目类别:
Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production
α细胞来源的细胞外囊泡和母体胰岛素的产生
  • 批准号:
    10681939
  • 财政年份:
    2023
  • 资助金额:
    $ 20.86万
  • 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
  • 批准号:
    10427574
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis
线粒体回补-回补对α细胞胰高血糖素分泌的调节
  • 批准号:
    10607392
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Arginine regulation of alpha cell proliferation and function
精氨酸调节α细胞增殖和功能
  • 批准号:
    10609909
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
  • 批准号:
    10675646
  • 财政年份:
    2022
  • 资助金额:
    $ 20.86万
  • 项目类别:
Elucidating alpha cell defects in human type 1 diabetes using precision cut pancreas slice-on-a-chip coupled with high spatio-temporal microscopy
使用精密切割的胰腺切片结合高时空显微镜阐明人类 1 型糖尿病的 α 细胞缺陷
  • 批准号:
    457552
  • 财政年份:
    2021
  • 资助金额:
    $ 20.86万
  • 项目类别:
    Studentship Programs
Defining alpha-cell proglucagon processing for type 2 diabetes treatment
定义 2 型糖尿病治疗的 α 细胞胰高血糖素原加工过程
  • 批准号:
    10331361
  • 财政年份:
    2020
  • 资助金额:
    $ 20.86万
  • 项目类别:
In vivo systems to discover mechanisms regulating human islet alpha cell function
体内系统发现调节人类胰岛α细胞功能的机制
  • 批准号:
    10623306
  • 财政年份:
    2020
  • 资助金额:
    $ 20.86万
  • 项目类别:
Deciphering alpha-cell heterogeneity using a novel reporter mouse
使用新型报告小鼠解读α细胞异质性
  • 批准号:
    20K08895
  • 财政年份:
    2020
  • 资助金额:
    $ 20.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了