Role of RIP2 in Biodefense Against Listeria Infection
RIP2 在针对李斯特菌感染的生物防御中的作用
基本信息
- 批准号:7055303
- 负责人:
- 金额:$ 33.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-05-15 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:ListeriaListeria infectionsbiological signal transductioncell differentiationcytokineenzyme activityenzyme mechanismgenetically modified animalsglycopeptideshelper T lymphocyteimmune responseimmunityinterferon gammainterleukin 12laboratory mouseleukocyte activation /transformationmacrophageserine threonine protein kinasesugar acids
项目摘要
DESCRIPTION (provided by applicant): The long-term objective of this proposal is to gain insight into the mechanisms of action of the receptor interacting protein 2 (RIP2) in host biodefense against Listeria monocytogenes infection. RIP2 is a member of the RIP family of serine/threonine (Ser/Thr) kinases. It has been implicated in the signal transduction pathways activated by the Nod receptor family proteins, potential receptors for intracellular pathogens. We recently created knockout mice lacking the RIP2 gene, and found that RIP2-/- mice are severely impaired in their ability to defend against infection with L. monocytogenes. Our preliminary results also indicated that RIP2-/- macrophages have lost their ability to respond to muramyl dipeptide (MDP), the minimal immunostimulatory subunit of peptidoglycan from gram positive bacteria. In addition, RIP2-/- T helper 1 (Thl) and natural killer (NK) cells have reduced interferon gamma (IFN-gamma) production upon IL-12 stimulation. We hypothesize that RIP2 may be involved in multiple signaling and cellular events to coordinate innate and adaptive immune responses in host biodefense against pathogen infection. We propose experiments to investigate RIP2- mediated signal transduction pathways and to determine the in vivo role of RIP2 in immune responses during pathogen infections. First, we hypothesize that RIP2 is involved in MDP-induced activation of innate immune responses. We will determine the role and the mechanism of RIP2 in mediating signal transduction and cytokine production by macrophages in response to MDP stimulation. Second, we hypothesize that RIP2 is involved in Thl differentiation by modulating the activity of IL-12-induced STAT4 activation and interferon gamma (IFN-gamma) production. We will first confirm the intrinsic defects of RIP2-/- Thl cells, and then explore potential signaling events where RIP2 might be involved in IL-12-induced STAT4 activation and interferon IFN-(, production. Third, we hypothesize that RIP2 is involved in host defense against microbial infections by affecting both innate and adaptive immune responses. We will determine the susceptibility of RIP2-/- mice to gram-positive and gram-negative extracellular and intracellular bacteria to understand the role of RIP2 in determining the pathogen specificity. We will also use L. monocytogenes infection of RIP2-/- mice as a model to determine the contribution of RIP2 in innate and adaptive immune responses against microbial infections. We believe that the insights obtained from these studies will provide new knowledge about pathogen recognition and coordination between innate and adaptive immune systems, and suggest new avenues of immunologic intervention to prevent and treat many human infectious diseases.
描述(由申请方提供):本提案的长期目标是深入了解受体相互作用蛋白2(RIP 2)在宿主生物防御单核细胞增生李斯特菌感染中的作用机制。RIP 2是丝氨酸/苏氨酸(Ser/Thr)激酶的RIP家族的成员。它涉及由Nod受体家族蛋白激活的信号转导途径,Nod受体家族蛋白是细胞内病原体的潜在受体。我们最近创造了缺乏RIP 2基因的敲除小鼠,发现RIP 2-/-小鼠在抵御L.单核细胞增多症我们的初步结果还表明,RIP 2-/-巨噬细胞已经失去了对胞壁酰二肽(MDP)的反应能力,MDP是革兰氏阳性菌肽聚糖的最小免疫刺激亚基。此外,RIP 2-/- T辅助1(Thl)和自然杀伤(NK)细胞在IL-12刺激后具有减少的干扰素γ(IFN-γ)产生。我们推测RIP 2可能参与多种信号传导和细胞事件,以协调宿主对病原体感染的生物防御中的先天性和适应性免疫应答。我们提出的实验研究RIP 2介导的信号转导途径,并确定在病原体感染的免疫反应中RIP 2在体内的作用。首先,我们假设RIP 2参与了MDP诱导的先天免疫应答的激活。我们将确定RIP 2在介导巨噬细胞对MDP刺激的信号转导和细胞因子产生中的作用和机制。其次,我们假设RIP 2通过调节IL-12诱导的STAT 4活化和干扰素γ(IFN-γ)产生的活性参与Thl分化。我们将首先确认RIP 2-/- Thl细胞的内在缺陷,然后探索RIP 2可能参与IL-12诱导的STAT 4活化和干扰素IFN-α产生的潜在信号传导事件。第三,我们假设RIP 2通过影响先天性和适应性免疫应答参与宿主对微生物感染的防御。我们将确定RIP 2-/-小鼠对革兰氏阳性和革兰氏阴性细胞外和细胞内细菌的敏感性,以了解RIP 2在确定病原体特异性中的作用。我们也将使用L。在一个实施方案中,使用RIP 2-/-小鼠的单核细胞增多症感染作为模型来确定RIP 2在针对微生物感染的先天性和适应性免疫应答中的贡献。我们相信,从这些研究中获得的见解将提供有关病原体识别和先天性和适应性免疫系统之间协调的新知识,并提出预防和治疗许多人类感染性疾病的免疫干预新途径。
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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GENHONG CHENG其他文献
GENHONG CHENG的其他文献
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{{ truncateString('GENHONG CHENG', 18)}}的其他基金
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- 批准号:
10222540 - 财政年份:2020
- 资助金额:
$ 33.95万 - 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
- 批准号:
10174522 - 财政年份:2020
- 资助金额:
$ 33.95万 - 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
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10461773 - 财政年份:2020
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Genetic evolution, pathogenesis and immune responses in mother to child transmission of ZIKV
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10388193 - 财政年份:2018
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$ 33.95万 - 项目类别:
Genetic evolution, pathogenesis and immune responses in mother to child transmission of ZIKV
ZIKV 母婴传播的遗传进化、发病机制和免疫反应
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9925059 - 财政年份:2018
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IKKa-Dependent Negative Feedback Control of Non-Canonical NF-kB Activation
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8039043 - 财政年份:2011
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IKKa-Dependent Negative Feedback Control of Non-Canonical NF-kB Activation
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8208992 - 财政年份:2011
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Mitiagrion of Radiation Damage by Mechanisms of Innate Immune Regulation
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8011751 - 财政年份:2010
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7741382 - 财政年份:2009
- 资助金额:
$ 33.95万 - 项目类别:
Role of IRF3 and RXRa Crosstalk in Host Response to Viral Infections
IRF3 和 RXRa 串扰在宿主对病毒感染的反应中的作用
- 批准号:
8091282 - 财政年份:2009
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