IRAK Family Function in Bacterial Infection
IRAK 家族在细菌感染中的功能
基本信息
- 批准号:6361102
- 负责人:
- 金额:$ 26.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-30 至 2002-09-29
- 项目状态:已结题
- 来源:
- 关键词:Escherichia coli RNase protection assay Streptococcus pneumoniae bacteria infection mechanism bacterial disease biological signal transduction blood cell count cellular immunity cytokine receptors disease /disorder model enzyme linked immunosorbent assay genetically modified animals host organism interaction immunoprecipitation inflammation interleukin 1 laboratory mouse lipopolysaccharides peritonitis protein kinase protein localization protein structure function tissue /cell culture
项目摘要
DESCRIPTION (provided by applicant): Infection represents one of the most
fundamental threats to host integrity. When a bacterial pathogen breaches an
epithelial barrier, the host innate immune system detects the attack and
triggers a response to contain and eliminate the invader. Cellular sensors,
such as macrophages and dendritic cells, detect pathogen through receptors that
recognize bacterial macromolecules. These cells then mount a proinflammatory
reaction that leads to cellular responses that contain and eliminate the
infection. Thus, the innate immune response contains both afferent
(pathogen-sensing) and efferent (proinflammatory) limbs. The Toll/IL-1 signal
transduction pathway mediates both arms of this innate response to infection.
This conserved signaling cascade consists of the proteins MyD88, the
interleukin-1 receptor-associated kinase (IRAK) family of molecules (IRAK,
IRAK2, and IRAK-M) and the tumor necrosis factor associated factor 6. It
processes signals from at least 10 Toll-like receptors (TLRs) and three IL-1
receptor family members (IL-1, IL-18, and T1/ST2), distributing them to
multiple downstream targets, including NF-kB and several mitogen activated
protein kinase cascades. We have genetically deleted IRAK, the primary proximal
kinase in this pathway, in mice. IRAK-deficient animals and macrophages exhibit
impaired responses to lipopolysaccharide (LPS), peptidoglycan (PGN), and
lipotechoic acid (LTA), and CpG DNA, bacterial molecules that activate the
afferent arm of innate immunity through TLR4 and TLR2. These mice also exhibit
attenuated proinflammatory (efferent) responses due to disrupted IL-1 and IL-18
signaling. The overall objective of this proposal is to determine IRAK function
in the host response to Gram-negative and Gram-positive infections. Aim 1 is to
determine the role of IRAK in the acute in vivo response to Gram-negative and
Gram-positive infections. We will subject IRAK knockout (KO) animals to
increasingly complex models of these infections using toxin challenges,
stimulation with heat-killed bacteria, and E. coli and S. pneumoniae
peritonitis and sepsis. Aim 2 is to isolate IRAK function genetically to either
the TLR4 or lL-1 receptor pathway and compare the responses of double and
single KO mice to LPS stimulation, heat killed E. coli, and E. coli
peritonitis. Aim 3 is to determine the contributions of IRAK2 and IRAK-M to
residual TLR signaling in IRAK-deficient cells, as deletion of IRAK impairs,
but does not completely abrogate signaling. These studies will provide
fundamental new information about the role of IRAK in the innate immune
response to acute bacterial infection and may eventually lead to the
development of strategies to modulate deleterious aspects of this response.
描述(由申请方提供):感染是最常见的
对主机完整性的根本威胁。当细菌病原体侵入
上皮屏障,宿主先天免疫系统检测攻击和
触发一个反应来控制并消灭入侵者。蜂窝传感器,
例如巨噬细胞和树突细胞,通过受体检测病原体,所述受体
识别细菌大分子。然后这些细胞形成一个促炎性
导致细胞反应的反应,该反应包含并消除
感染因此,先天性免疫应答包含两种传入
(病原体感应)和传出(促炎)肢。Toll/IL-1信号
转导途径介导这种对感染的先天性应答的两个分支。
这种保守的信号级联反应由蛋白MyD 88、
白细胞介素-1受体相关激酶(IRAK)分子家族(IRAK,
IRAK 2和IRAK-M)和肿瘤坏死因子相关因子6。它
处理来自至少10种Toll样受体(TLR)和3种IL-1的信号
受体家族成员(IL-1、IL-18和T1/ST 2),将它们分布到
多个下游靶点,包括NF-κ B和几种有丝分裂原激活
蛋白激酶级联反应。我们已经从基因上删除了IRAK,一种主要的近端
激酶在这条途径中的作用。IRAK缺陷动物和巨噬细胞表现出
对脂多糖(LPS)、肽聚糖(PGN)和
脂儿茶酸(LTA)和CpG DNA,这两种细菌分子可激活
通过TLR 4和TLR 2介导先天免疫的传入臂。这些小鼠还表现出
由于破坏的IL-1和IL-18而减弱的促炎(传出)反应
发信号。本建议书的总体目标是确定伊拉克共和国的职能
在宿主对革兰氏阴性菌和革兰氏阳性菌感染的反应中。目的1是
确定IRAK在革兰氏阴性菌急性体内反应中的作用,以及
革兰氏阳性菌感染。我们将对IRAK基因敲除(KO)动物进行
使用毒素攻击的这些感染的日益复杂的模型,
用热灭活菌刺激; coli和革兰氏阳性菌S.肺炎
腹膜炎和脓毒症。目的2是从基因上分离IRAK的功能
TLR 4或IL-1受体通路,比较双通道和
单基因敲除小鼠以LPS刺激,热杀E. coli和E.杆菌
腹膜炎。目标3是确定IRAK 2和IRAK-M对以下方面的贡献
在IRAK缺陷细胞中的残余TLR信号传导,由于IRAK的缺失损害,
但不完全废除信令。这些研究将提供
关于IRAK在先天性免疫中作用的基本新信息
对急性细菌感染的反应,并可能最终导致
制定策略以调节这种反应的有害方面。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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JAMES Alanson THOMAS其他文献
JAMES Alanson THOMAS的其他文献
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{{ truncateString('JAMES Alanson THOMAS', 18)}}的其他基金
AGING EFFECT ON PROTEIN S THIOLATION/DETHIOLATION
老化对蛋白质硫醇化/脱硫醇化的影响
- 批准号:
2409879 - 财政年份:1997
- 资助金额:
$ 26.74万 - 项目类别:
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