MAST CELLS IN INNATE IMMUNITY AGAINST BACTERIAL INFECTIO

描述(改编自申请人的摘要)：肥大细胞是 功能多样和解剖上无处不在的免疫成分 在过敏和免疫学方面具有良好作用的系统。肥大细胞是 能够调节宿主对革兰氏阴性菌的先天免疫防御 细菌通过以下途径增加感染部位的中性粒细胞的流入 肿瘤坏死因子的释放(《自然》，381：77-80,1996)。进一步肥大细胞-细菌 肥大细胞表面受体CD48与细菌的相互作用 黏附分子FimH。JAK-3基因缺陷的肥大细胞和JAK-3基因缺陷小鼠 降低了对抗革兰氏阴性细菌的能力。假设是 被调查的是涉及特定生化信号转导事件的 蛋白酪氨酸激酶JAK3是由肥大细胞-革兰氏阴性触发的 细菌之间的相互作用。建议进行机理研究以进一步阐明 肥大细胞在宿主防御中的作用。为此，PI将测试特定的 假设采用了成熟的体外和体内模型系统。特定的 目标1将测试肥大细胞对革兰氏菌的反应能力 阴性细菌感染，并将成为信号转导的特征 由革兰氏阴性细菌与肥大细胞相互作用引发的事件。 在具体目标2下，PI将试图将这一知识转化为 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杆菌的防御增强 阴性细菌感染。具体地说，体外和体内效应 干细胞因子(SCF)--JAK-STAT通路的刺激物--对肥大细胞的作用 将检查对FimH阳性革兰氏阴性细菌的反应。这些 研究将提供关于肥大细胞参与 对致病性革兰氏阴性细菌的天然宿主防御。

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.