Anti-inflammatory role of MUC1 mucin
MUC1粘蛋白的抗炎作用
基本信息
- 批准号:6964661
- 负责人:
- 金额:$ 51.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-02-03 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:Pseudomonas aeruginosaantiinflammatory agentsbacteria infection mechanismbiological signal transductioncystic fibrosiscytokineflagellingene expressiongenetically modified animalshost organism interactionimmunoprecipitationlaboratory mouselung lavagemacrophagemucinsneutrophilopportunistic infectionsprotein bindingprotein protein interactionrespiratory epitheliumrespiratory infectionssite directed mutagenesissmall interfering RNAtoll like receptorwestern blottings
项目摘要
DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of clinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, the major cause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in the respiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF patients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of different theories have been proposed to account for the etiology of CF. Our laboratory made the interesting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structure of the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminary studies showed that, compared with wild type mice, Muc1 knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokines in bronchoalveolar lavage fluid following PA flagellin stimulation. Interestingly, TLR5 is another cell surface receptor that generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationship between MUC1 and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis that MUC1 is an anti-inflammatory cell surface receptor that acts, at least in part, through antagonism of flagellin-TLR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuates TLR5 signal transduction. Successful completion of this project will provide important insights for the role of MUC1 in inflammation, innate immunity, and the early stages of PA infection in CF.
描述(由申请人提供):铜绿假单胞菌(PA)是一种机会性细菌病原体,导致许多临床上重要的肺部疾病,包括肺炎和囊性纤维化(CF)。 就 CF 而言,患者发病和死亡的主要原因是气道阻塞,这是由于粘稠且顽固的粘液严重感染 PA 所致。 由于 PA 暴露发生在正常人和 CF 个体的呼吸系统中,因此 CF 患者中这种病原体的“选择性”感染表明存在非 CF 气道中不存在的致病机制。 已经提出了许多不同的理论来解释 CF 的病因。 我们实验室做了一个有趣的观察,气道上皮细胞表面的MUC1粘蛋白是通过细菌鞭毛蛋白介导的PA的特异性结合位点。 MUC1 糖蛋白的结构表明,它作为受体在与鞭毛蛋白相互作用后在细胞内传递信号。 使用基因修饰阻断MUC1表达的小鼠(MUC1敲除小鼠),我们的初步研究表明,与野生型小鼠相比,Muc1敲除小鼠在PA鞭毛蛋白刺激后表现出肺部PA清除率增加,气道白细胞募集更多,支气管肺泡灌洗液中促炎细胞因子水平更高。 有趣的是,TLR5 是另一种细胞表面受体,在与鞭毛蛋白结合后产生细胞内信号传导途径。 基于这种相似性,我们进行了额外的实验来研究 MUC1 和 TLR5 之间的功能关系。 我们观察到MUC1的表达抑制正常肺细胞中的鞭毛蛋白-TLR5信号通路,但不抑制CF气道上皮细胞。 基于这些结果,我们提出了这样的假设:MUC1 是一种抗炎细胞表面受体,其至少部分通过拮抗鞭毛蛋白-TLR5 信号传导发挥作用。 在本提案中,我们将通过确定 MUC1 减弱 TLR5 信号转导的机制来测试我们的理论。 该项目的成功完成将为了解 MUC1 在炎症、先天免疫以及 CF 中 PA 感染的早期阶段的作用提供重要的见解。
项目成果
期刊论文数量(0)
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KWANG CHUL KIM其他文献
KWANG CHUL KIM的其他文献
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{{ truncateString('KWANG CHUL KIM', 18)}}的其他基金
ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA
MUC1 在过敏性哮喘发生中的作用
- 批准号:
7860294 - 财政年份:2009
- 资助金额:
$ 51.25万 - 项目类别:
ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA
MUC1 在过敏性哮喘发生中的作用
- 批准号:
7388434 - 财政年份:2009
- 资助金额:
$ 51.25万 - 项目类别:
NEGATIVE REGULATORY ELEMENT OF HAMSTER MUC 1 PROMOTER
仓鼠 MUC 1 启动子的负调控元件
- 批准号:
6629037 - 财政年份:2000
- 资助金额:
$ 51.25万 - 项目类别:
NEGATIVE REGULATORY ELEMENT OF HAMSTER MUC 1 PROMOTER
仓鼠 MUC 1 启动子的负调控元件
- 批准号:
6027280 - 财政年份:2000
- 资助金额:
$ 51.25万 - 项目类别:
NEGATIVE REGULATORY ELEMENT OF HAMSTER MUC 1 PROMOTER
仓鼠 MUC 1 启动子的负调控元件
- 批准号:
6351583 - 财政年份:2000
- 资助金额:
$ 51.25万 - 项目类别:
NEGATIVE REGULATORY ELEMENT OF HAMSTER MUC 1 PROMOTER
仓鼠 MUC 1 启动子的负调控元件
- 批准号:
6499017 - 财政年份:2000
- 资助金额:
$ 51.25万 - 项目类别:
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