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.

先天免疫系统通过招募中性粒细胞在及时和协调的方式。多种趋化因子以响应感染表示，调解这一点过程，首先将中性粒细胞募集到感染部位，然后激活它们以释放细胞毒性颗粒酶和超氧化物以杀死有问题的微生物。招聘受损和/或受损激活导致感染的分辨率不完全，而不受控制的募集和/或持续激活导致健康组织和疾病的破坏。目前，分子机制通过趋化因子的哪种协调作用介导中性粒细胞功能尚不清楚。在老鼠中，趋化因子KC/CXCL1和MIP2/CXCL2坐标中性粒细胞功能。我们的初步数据表明 KC和MIP2作为单体和二聚体存在，最有趣的是，也是异二聚体。在此R21中探索性授予，我们将检验以下假设：KC和MIP2的结构和功能特性 KC和MIP2之间的串扰在中性粒细胞功能中起着非冗余作用。在 AIM 1，我们将表征KC和MIP2媒体腹膜中性粒细胞招募如何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会影响中性粒细胞水平并定义其激活微生物杀死的表型。在AIM 2中，我们将表征招募的微生物杀戮活动通过表征颗粒蛋白酶和超氧化物活性来表征中性粒细胞。在AIM 3中，我们将描述 CXCR2介导的G蛋白和β-arrest蛋白信号通路和β-的KC和MIP2活性抑制蛋白介导的接收器内吞作用。我们表征的假设和研究策略趋化因子串扰以及我们的初步数据，表明KC和MIP2的募集概况可以是非常不同的是新颖的。这些研究的成功完成将提供关键的机械见解进入趋化因子协同作用和中性粒细胞表型之间的因果关系，并充当未来开发新颖有效的治疗靶标，以治疗传染病的框架。