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Chemokine Synergy and Neutrophil Function

趋化因子协同作用和中性粒细胞功能

基本信息

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
项目类别：
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

项目摘要

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.

先天免疫系统高度进化，可以通过招募中性粒细胞来对抗传染性病原体。及时、协调地进行。针对感染而表达的多种趋化因子介导了这一过程过程中，首先将中性粒细胞募集到感染部位，然后激活它们释放细胞毒素颗粒酶和超氧化物杀死有害微生物。招募受损和/或受损激活导致感染不完全解决，而不受控制的募集和/或持续激活会导致健康组织的破坏和疾病。此时，分子机制通过趋化因子的协调作用介导中性粒细胞功能尚不清楚。在小鼠中，趋化因子 KC/CXCL1 和 MIP2/CXCL2 协调中性粒细胞功能。我们的初步数据表明 KC 和 MIP2 以单体和二聚体形式存在，最有趣的是，也以异二聚体形式存在。在这个R21 探索性资助，我们将测试 KC 和 MIP2 的结构和功能特性的假设 KC和MIP2之间的串扰在介导中性粒细胞功能中发挥非冗余作用。在目标 1，我们将描述 KC 和 MIP2 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、二聚体和异二聚体水平的变化影响中性粒细胞水平并定义其激活杀灭微生物的表型。在目标 2 中，我们将表征招募的微生物杀灭活性通过表征颗粒蛋白酶和超氧化物活性来检测中性粒细胞。在目标 3 中，我们将描述 CXCR2 介导的 G 蛋白和 β-arrestin 信号通路以及 β- 的 KC 和 MIP2 活性抑制蛋白介导的受体内吞作用。我们的假设和表征研究策略趋化因子串扰，我们的初步数据显示 KC 和 MIP2 的招募概况可以非常不同，都很新颖。成功完成这些研究将提供关键的机制见解研究趋化因子协同作用与中性粒细胞表型之间的因果关系，并作为未来开发治疗传染病的新颖有效的治疗靶点的框架。