Neutrophil Chemotaxis in Autoinflammation

描述（由申请人提供）：自身炎性综合征包括一组异质性遗传性疾病，其特征在于涉及先天免疫系统细胞的无菌性炎症的反复发作。这些疾病的一个标志是中性粒细胞向组织中的异常浸润，表明中性粒细胞运输或运动的缺陷可能有助于疾病的发病机制。炎症反应过程中的关键步骤包括白细胞极化和向化学引诱物方向迁移。我们工作的长期目标是定义调节体外中性粒细胞趋化性的信号通路，并通过使用zebraflsh作为模型系统来检查体内中性粒细胞趋化性和炎症来理解这些机制对慢性炎症性疾病的影响。对调节中性粒细胞趋化性的基本机制的了解应该为自身炎症综合征和其他炎症是发病机制核心的疾病状态提供治疗靶点。我们实验室最近的研究表明，钙依赖性蛋白酶钙蛋白酶对中性粒细胞趋化性至关重要。我们最近的研究还表明，磷酸肌醇磷酸激酶，PIPKI γ，与钙蛋白酶2相互作用，是趋化性所必需的。我们建议测试的假设，PSTPIP1和其他蛋白质突变的自身炎症综合征调节信号通路的细胞迁移和趋化性的关键，包括一种新的途径介导的钙蛋白酶2和PIPKIgamma，从而影响中性粒细胞的趋化性和炎症在体内。具体目标：一。阐明钙蛋白酶2和PIPKI γ如何调节中性粒细胞趋化性和炎症。我们建议测试的假设，钙蛋白酶2和PIPKIgamma功能的正反馈回路，调节中性粒细胞趋化性和炎症。二.研究PSTPIP1，一种在PAPA综合征中突变的衔接蛋白，如何调节中性粒细胞趋化性和炎症。我们建议检查钙蛋白酶2和PSTPIP1之间的相互作用，以及其在中性粒细胞趋化和炎症过程中的作用。三.以zebraflsh为模型系统研究中性粒细胞趋化性和体内炎症反应。靶向和非靶向方法将用于鉴定体内参与中性粒细胞趋化性和炎症的关键信号通路。我们建议对斑马鱼PSTPIP1进行表征，并开发自体炎症的疾病模型。

DESCRIPTION (provided by applicant): Autoinflammatory syndromes comprise a heterogeneous group of inherited disorders characterized by recurrent episodes of aseptic inflammation involving cells of the innate immune system. A hallmark of these disorders is the abnormal infiltration of neutrophils into tissues, suggesting that defects in neutrophil trafficking or motility may contribute to disease pathogenesis. Critical steps during the inflammatory response include leukocyte polarization and migration in the direction of chemoattractant. The long term goal of our work is to define signaling pathways that regulate neutrophil chemotaxis in vitro, and to understand the implications of these mechanisms to chronic inflammatory disease by using zebraflsh as a model system to examine neutrophil chemotaxis and inflammation in vivo. Knowledge of the basic mechanisms that regulate neutrophil chemotaxis should provide therapeutic targets for autoinflammatory syndromes and other disease states in which inflammation is central to pathogenesis. Recent studies from our laboratory demonstrate that the calcium-dependent protease calpain is critical for neutrophil chemotaxis. Our recent studies also show that the phosphatyidylinositol phosphate kinase, PIPKIgamma, interacts with calpain 2 and is required for chemotaxis. We propose to test the hypothesis that PSTPIP1 and other proteins mutated in autoinflammatory syndromes modulate signaling pathways critical for cell migration and chemotaxis, including a novel pathway mediated by calpain 2 and PIPKIgamma, thereby affecting neutrophil chemotaxis and inflammation in vivo. Specific Aims: I. Elucidate how calpain 2 and PIPKIgamma regulate neutrophil chemotaxis and inflammation. We propose to test the hypothesis that calpain 2 and PIPKIgamma function in a positive feedback loop that regulates neutrophil chemotaxis and inflammation. II. Examine how PSTPIP1, an adaptor protein mutated in PAPA syndrome, modulates neutrophil chemotaxis and inflammation. We propose to examine the interaction between calpain 2 and PSTPIP1, and its role during neutrophil chemotaxis and inflammation. III. Use zebraflsh as a model system to examine neutrophil chemotaxis and inflammation in vivo. Both targeted and non-targeted approaches will be used to identify key signaling pathways involved in neutrophil chemotaxis and inflammation in vivo. We propose to characterize zebrafish PSTPIP1 and develop disease models of autoinflammation.