Chemokine Synergy and Neutrophil Function

趋化因子协同作用和中性粒细胞功能

• 批准号: 9193997
• 负责人: Krishna Rajarathnam
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193997
• 关键词: Address; Bacteria; Bacterial Infections; Binding; Biochemical; Blood; CXCL1 gene; CXCL2 gene; Clinical; Communicable Diseases; Cytoplasmic Granules; Data; Development; Disease; Dose; Enzymes; Focal Infection; Future; GTP-Binding Proteins; Grant; Host Defense; Hour; IL8RB gene; Immune system; Infection; Inflammatory; Interleukin-8B Receptor; Knockout Mice; Knowledge; Mediating; Microbe; Molecular; Mus; Neutrophil Infiltration; Peptide Hydrolases; Peptides; Peripheral; Peritoneal; Peritoneum; Phenotype; Physiological; Play; Process; Property; Reactive Oxygen Species; Recording of previous events; Recruitment Activity; Research; Resolution; Role; Signal Pathway; Signal Transduction; Site; Superoxides; Testing; Therapeutic; Time; Tissues; Variant; base; beta-arrestin; cell injury; chemokine; cytotoxic; design; dimer; drug development; in vivo; insight; killings; microbial; monomer; neutrophil; novel; pathogen; public health relevance; receptor mediated endocytosis; response; success; therapeutic target; trafficking

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.

先天性免疫系统高度进化，通过招募中性粒细胞来对抗感染性病原体。 及时和协调的方式。多种趋化因子，在感染反应中表达，介导这一过程。 这一过程，首先招募中性粒细胞到感染部位，然后激活它们释放细胞毒性， 颗粒酶和超氧化物来杀死入侵的微生物。招募受损和/或受损 激活导致感染不完全消退，而不受控制的募集和/或持续的 激活导致健康组织的破坏和疾病。此时，分子机制 哪些趋化因子的协调作用介导嗜中性粒细胞功能尚不清楚。在小鼠中， 趋化因子KC/CXCL 1和MIP 2/CXCL 2协调嗜中性粒细胞功能。初步数据显示， KC和MIP 2以单体和二聚体存在，最有趣的是，也以异源二聚体存在。在R21中 探索性赠款，我们将测试的假设，KC和MIP 2的结构和功能特性， KC和MIP 2之间的相互作用在介导中性粒细胞功能中起非冗余作用。在 目的1，我们将描述KC和MIP 2如何介导腹膜中性粒细胞募集，以建立 趋化因子和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、二聚体和异源二聚体水平的变化影响中性粒细胞水平并确定其活化 用于微生物杀灭的表型。在目标2中，我们将表征所招募的化合物的微生物杀灭活性。 中性粒细胞通过表征颗粒蛋白酶和超氧化物活性。在目标3中，我们将描述 KC和MIP 2对CXCR 2介导的G蛋白和β-抑制蛋白信号通路的活性以及β- 抑制蛋白介导的受体内吞作用。我们的假设和研究策略， 我们的初步数据显示，KC和MIP 2的募集谱可以被 非常不同的是小说。成功完成这些研究将提供关键的机制见解 趋化因子协同作用和中性粒细胞表型之间的因果关系，并作为一个 为未来开发治疗传染病的新型有效治疗靶点提供了框架。