LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING
粘膜重塑中的淋巴细胞/上皮相互作用
基本信息
- 批准号:6325905
- 负责人:
- 金额:$ 32.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-07-01 至 2001-06-30
- 项目状态:已结题
- 来源:
- 关键词:JAK kinase Mycoplasma asthma biomarker bronchial mucus cell cell interaction cell differentiation cell population study cellular pathology collagenase flow cytometry gel mobility shift assay immunocytochemistry immunofluorescence technique inflammation interleukin 9 laboratory mouse lymphocyte metalloendopeptidases mucins mycoplasmal pneumonia polymerase chain reaction respiratory epithelium respiratory infections transcription factor
项目摘要
The epithelium of chronically inflamed airways is characterized by mucus hypersecretion and shows 2 relevant adaptations: (a) mucous cell metaplasia, whereby individual epithelial cells differentiate to express mucin and (b) epithelial remodeling whereby the entire epithelial tissue layer becomes convoluted, invading connective tissue to form mucous crypts and glands. To identify molecular mechanisms underlying these changes requires the use of biochemical markers. Mucin can be considered a marker for mucous metaplasia as mucous differentiation is dependent on mucin gene expression. Metalloproteinases can be considered markers for epithelial remodeling as morphogenetic processes requiring connective tissue degradation are dependent on these enzymes. Seeking stimuli potentially controlling mucin and metalloproteinase expression in the inflamed airway we tested the effect of lymphocyte-derived cytokines. Product of both mixed lymphocyte reactions and fluid from asthmatic airways stimulated expression of the two markers at the RNA level. Experiments described below indicate that the Th2 cell mediator IL-9 is a major mucin stimulus in asthmatic airway fluid and that the T cell surface marker OX-47 (EMMPRIN) strongly stimulates metalloproteinases 1 and 9. Based on these relationships, we hypothesize that activated T cells in inflamed airways control mucous metaplasia and epithelial remodeling via IL-9 and EMMPRIN. Specific aim 1 will use mutant mice to determine which lymphocyte populations are required for M. pulmonis-induced mucin (Muc 5ac) and metalloproteinase (MMP-9) gene activation. Specific aim 2, using chemical inhibitors, dominant negative mutants and chimeric IL-9 receptor constructs, will test the hypothesis that IL-9 stimulates MUC5 AC in human bronchial epithelial cells via intersecting JAK-STAT and MAPK signaling pathways. Specific aim 3, using biochemical inhibitors, dominant negative mutants and a novel mutagenesis approach, will test the hypothesis that EMMPRIN stimulates MMP-1 in human fibroblasts via a p38-dependent mechanisms and will identify key elements of EMMPRIN-MMP signaling.
慢性炎症的呼吸道上皮以粘液高分泌为特征,并表现出两种相关的适应性:(A)粘液细胞化生,单个上皮细胞分化为表达粘蛋白;(B)上皮重塑,整个上皮组织层变得卷曲,侵袭结缔组织,形成粘液腺和腺体。要确定这些变化背后的分子机制,需要使用生化标记物。粘蛋白可以被认为是粘液化生的标志,因为粘液的分化依赖于粘蛋白基因的表达。金属蛋白酶可以被认为是上皮重塑的标志,因为需要结缔组织降解的形态发生过程依赖于这些酶。为了寻找潜在的控制炎症呼吸道粘蛋白和金属蛋白酶表达的刺激,我们测试了淋巴细胞衍生的细胞因子的作用。混合淋巴细胞反应产物和哮喘呼吸道分泌液均在RNA水平刺激这两种标志物的表达。实验表明,Th2细胞介质IL-9是哮喘气道液中主要的粘蛋白刺激因子,T细胞表面标志OX-47(EMMPRIN)强烈刺激金属蛋白酶1和9。基于这些关系,我们推测炎症气道中活化的T细胞通过IL-9和EMMPRIN控制粘液化生和上皮重塑。特定目的1将使用突变小鼠来确定哪些淋巴细胞群是肺支原体诱导的粘蛋白(MUC 5AC)和金属蛋白酶(MMP9)基因激活所必需的。具体目标2,利用化学抑制剂、显性负性突变体和嵌合的IL-9受体结构,将验证IL-9通过交叉JAK-STAT和MAPK信号通路刺激人支气管上皮细胞MUC5AC的假设。利用生化抑制剂、显性负性突变体和一种新的突变方法,将验证EMMPRIN通过p38依赖的机制刺激人成纤维细胞中MMP1的假说,并将确定EMMPRIN-MMPs信号的关键元件。
项目成果
期刊论文数量(0)
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CAROL B BASBAUM其他文献
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{{ truncateString('CAROL B BASBAUM', 18)}}的其他基金
Role of Airway Epithelium in Mycoplasma Pathogenesis
气道上皮在支原体发病机制中的作用
- 批准号:
6955248 - 财政年份:2004
- 资助金额:
$ 32.24万 - 项目类别:
Smoke-induced AP-1 controls mucous vs squamous phenotype
烟雾诱导的 AP-1 控制粘液与鳞状细胞表型
- 批准号:
6718687 - 财政年份:2004
- 资助金额:
$ 32.24万 - 项目类别:
LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING
粘膜重塑中的淋巴细胞/上皮相互作用
- 批准号:
6781168 - 财政年份:2003
- 资助金额:
$ 32.24万 - 项目类别:
Role of Chloride Channels in Mucin Production
氯离子通道在粘蛋白生产中的作用
- 批准号:
6606386 - 财政年份:2003
- 资助金额:
$ 32.24万 - 项目类别:
Role of Chloride Channels in Mucin Production
氯离子通道在粘蛋白生产中的作用
- 批准号:
6723666 - 财政年份:2003
- 资助金额:
$ 32.24万 - 项目类别:
LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING
粘膜重塑中的淋巴细胞/上皮相互作用
- 批准号:
6616334 - 财政年份:2002
- 资助金额:
$ 32.24万 - 项目类别:
LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING
粘膜重塑中的淋巴细胞/上皮相互作用
- 批准号:
6491087 - 财政年份:2001
- 资助金额:
$ 32.24万 - 项目类别:
LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING
粘膜重塑中的淋巴细胞/上皮相互作用
- 批准号:
6109555 - 财政年份:1999
- 资助金额:
$ 32.24万 - 项目类别:
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