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中文摘要
翻译
先天免疫系统是高度进化的,通过在体内招募中性粒细胞来对抗感染病原体 以及时和协调的方式。感染后表达的多种趋化因子介导了这一过程。 过程,首先将中性粒细胞招募到感染部位,然后激活它们释放细胞毒 颗粒酶和超氧化物以杀死有害微生物。招募受损和/或受损 激活会导致感染不完全消失,而不受控制的招募和/或持续 激活会导致健康组织的破坏和疾病。在这个时候,分子机制通过 趋化因子对中性粒细胞功能有哪些协同作用尚不清楚。在小鼠身上, 趋化因子KC/CXCL1和MIP2/CXCL2协调中性粒细胞功能。我们的初步数据显示, KC和MIP2以单体和二聚体的形式存在,最有趣的是,也以杂二聚体的形式存在。在此R21中 ,我们将检验KC和MIP2的结构和功能特性的假设 KC和MIP2之间的串扰在调节中性粒细胞功能中起着非多余的作用。在……里面 目的1,我们将表征KC和MIP2如何介导腹膜中性粒细胞募集,以建立 趋化因子与中性粒细胞水平之间的因果关系。更具体地说,我们将阐明如何 单体、二聚体和异二聚体水平的变化影响中性粒细胞水平并确定其激活。 微生物杀灭的表型。在目标2中,我们将表征招募的微生物的杀灭活性 中性粒细胞颗粒蛋白水解酶和超氧化物歧化酶活性的测定。在目标3中,我们将描述 CXCR2介导的G蛋白和β-arrestin信号通路的KC和MIP2活性及β- 芦荟素介导的受体内吞作用。我们的假设和研究策略 趋化因子串扰,我们的初步数据显示,KC和MIP2的招募简档可以 非常不同的是新奇的。这些研究的成功完成将提供重要的机械论见解 趋化因子协同作用和中性粒细胞表型之间的因果关系,并作为 未来开发新的和有效的治疗传染病的治疗靶点的框架。
英文摘要
The innate immune system is highly evolved to counter infectious pathogens by recruiting neutrophils in a timely and coordinated manner. Multiple chemokines, expressed in response to infection, mediate this process, by first recruiting neutrophils to the infection site, and then activating them to release cytotoxic granule enzymes and superoxide to kill the offending microbe. Impaired recruitment and/or impaired activation result in incomplete resolution of infection, whereas uncontrolled recruitment and/or sustained activation result in destruction of healthy tissue and disease. At this time, the molecular mechanisms by which coordinated action of chemokines mediate neutrophil function are not known. In mice, the chemokines KC/CXCL1 and MIP2/CXCL2 coordinate neutrophil function. Our preliminary data show that KC and MIP2 exist as monomers and dimers, and most interestingly, also as heterodimers. In this R21 exploratory grant, we will test the hypothesis that the structural and functional properties of KC and MIP2 and the crosstalk between KC and MIP2 play non-redundant roles in mediating neutrophil function. In Aim 1, we will characterize how KC and MIP2 mediate peritoneal neutrophil recruitment to establish the causal relationship between chemokine and neutrophil levels. More specifically, we will elucidate how changes in monomer, dimer, and heterodimer levels influence neutrophil levels and define its activation phenotype for microbial killing. In Aim 2, we will characterize the microbial killing activity of recruited neutrophils by characterizing granule protease and superoxide activities. In Aim 3, we will characterize the KC and MIP2 activities for CXCR2-mediated G-protein and β-arrestin signaling pathways and β- arrestin mediated receptor endocytosis. Our hypothesis and research strategy for characterizing chemokine crosstalk, and our preliminary data showing that recruitment profiles of KC and MIP2 can be very different are novel. Successful completion of these studies will provide critical mechanistic insights into the causal relationships between chemokine synergy and neutrophil phenotype, and serve as a framework for future development of novel and effective therapeutic targets to treat infectious diseases.
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Structural Basis of chemokine CXCL1 recognition with CXCR2 receptor
Structural Basis of chemokine CXCL1 recognition with CXCR2 receptor
Malvern MicroCal PEAQ Isothermal Titration Calorimeter
Chemokine CXCL17 and Mucosal Immunosurveillance
国内基金
海外基金
Segmented Filamentous Bacteria激活宿主免疫系统抑制其拮抗菌 Enterobacteriaceae维持菌群平衡及其机制研究
  • 批准号:
    81971557
  • 项目类别:
    面上项目
  • 资助金额:
    65.0万元
  • 批准年份:
    2019
  • 负责人:
    毛开睿
  • 依托单位:
电缆细菌(Cable bacteria)对水体沉积物有机污染的响应与调控机制