MAST CELLS IN INNATE IMMUNITY AGAINST BACTERIAL INFECTIO

肥大细胞对细菌感染具有先天免疫力

• 批准号: 6044742
• 负责人: RAVI MALAVIYA
• 金额: $ 27.78万
• 依托单位: PARKER HUGHES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044742
• 关键词: JAK kinase; bactericidal immunity; bone marrow; gene targeting; genetically modified animals; gram negative bacteria; human fetus tissue; laboratory mouse; mast cell; stem cell factor; tissue /cell culture; tumor necrosis factor alpha

Description (Adapted from the applicants' abstract): Mast cells are functionally versatile and anatomically ubiquitous elements of the immune system with well established roles in allergy and immunology. Mast cells are capable of modulating the hosts' innate immune defense against gram negative bacteria by augmenting the influx of neutrophils at sites of infection through the release of TNF (Nature, 381: 77-80, 1996). Further mast cell-bacteria interactions are mediated by the mast cell surface receptor CD48 and bacterial adhesion molecule FimH. JAK-3-deficient mast cells and JAK-3-deficient mice have reduced capacity to fight gram negative bacteria. The hypothesis to be investigated is that specific biochemical signal transduction events involving the protein tyrosine kinase JAK3 are triggered by mast cell-gram negative bacteria interactions. Mechanistic studies are proposed to further elucidate the role of mast cells in host defense. To this end, the PI will test specific hypotheses using well-established in vitro and in vivo model systems. Specific Aim #1 will test the ability of mast cells to mount a response against gram negative bacterial infections, and will characterize the signal transduction events triggered by the interaction of gram negative bacteria with mast cells. Under Specific Aim 2, the PI will attempt to translate this knowledge into a new strategy for more effective treatment of gram negative bacterial infections based upon cytokine stimulated potentiation of mast cell defenses against gram negative bacterial infections. Specifically, the in vitro and in vivo effects of stem cell factor (SCF), a stimulator of the JAK-STAT pathways, on mast cell responses against FimH positive gram negative bacteria will be examined. These studies will provide new insights regarding the participation of mast cells in innate host defense against pathogenic gram negative bacteria.

描述（改编自申请人摘要）：肥大细胞是 免疫系统中功能多样且解剖学上普遍存在的成分 系统在过敏和免疫学中具有良好的作用。肥大细胞 能够调节宿主对革兰氏阴性菌的先天免疫防御 通过增加感染部位中性粒细胞的流入， TNF的释放（Nature，381：77-80，1996）。其他肥大细胞-细菌 相互作用由肥大细胞表面受体CD 48和细菌介导。 粘附分子FimH。JAK-3缺陷肥大细胞和JAK-3缺陷小鼠 抵抗革兰氏阴性菌的能力降低。假设是 研究的是特定的生化信号转导事件， 蛋白酪氨酸激酶JAK 3由肥大细胞-革兰氏阴性 细菌相互作用机制研究建议进一步阐明 肥大细胞在宿主防御中的作用。为此，PI将测试特定的 使用完善的体外和体内模型系统的假设。具体 目标#1将测试肥大细胞对革兰氏阳性反应的能力 阴性细菌感染，并将表征信号转导 由革兰氏阴性菌与肥大细胞相互作用引发的事件。 根据具体目标2，PI将尝试将这些知识转化为 更有效治疗革兰氏阴性细菌感染的新策略 基于细胞因子刺激的肥大细胞对革兰氏阴性菌的防御增强， 阴性细菌感染。具体而言，体外和体内效应 干细胞因子（SCF）是JAK-STAT通路的刺激因子， 将检测针对FimH阳性革兰氏阴性细菌的应答。这些 研究将提供关于肥大细胞参与 先天宿主防御致病性革兰氏阴性细菌。