Optimizing phagocyte activity against antibiotic resistant pathogens

我们计划的研究将集中在广谱治疗耐药病原体的新方法上， 使用耐甲氧西林的S.金黄色葡萄球菌（MRSA）和铜绿假单胞菌（PA）。我们有 提供了吞噬细胞活性可以在体外和体内通过转录激活的原理证明。 调节因子HIF-1，并且HIF-1严重依赖于NF-κ B信号传导。他说，我们正在采取更广泛的观点， 我们发表的数据应用了小鼠遗传工具和传染病模型系统， 吞噬细胞中的其它受体信号传导、信号转导和转录控制途径， 适用于药理学操作以增强巨噬细胞和嗜中性粒细胞的抗菌能力。本质上 2005年，我们发现缺乏IKKa激酶调节NF-κ B活化的小鼠的炎症反应增加， 和杀虫活性。在目的1中，我们将使用体内和离体研究IKKa激酶在调节 吞噬细胞对MRSA和PA的杀菌和炎症反应，并探讨其与HIF-1介导的 细胞能量代谢在2010年的《自然免疫学》中，我们发现缺乏IKKP激酶调节NF κ B的小鼠， 与GAS相比，活化增加了IL-1 P/IL-1 R信号传导以增强嗜中性粒细胞数目和细菌防御。目标2 我们将使用离体和体内模型沿着特定的药理学拮抗剂来评估其作用 IKKp激酶和下游IL-ip/IL-1 R信号在调节吞噬细胞杀菌和炎症中的作用 对抗药性细菌病原体的反应。在2006年的《科学》中，我们观察到A3腺苷受体的作用， 在本提案的目标3中，我们将研究A3受体信号在调节中性粒细胞趋化性中的作用。 吞噬细胞对MRSA和PA的杀菌和炎症反应。在2011年的《免疫学》中，我们发现P2 X7受体 介导ATP检测和巨噬细胞介导的宿主防御B。在目标4中，我们将探讨 ATP/P2 X7受体信号传导和炎性小体激活在调节吞噬细胞杀菌和 炎症反应

Our proposed research will focus on new approaches to broad-spectrum therapy for antibiotic-resistant pathogens, using as our primary model organisms methicillin-resistant S. aureus (MRSA) and P. aeruginosa (PA). We have provided proof-of-principle that phagocytic cell activity can be activated in vitro and in vivo through transcriptional regulator HIF-1 and that HIF-1 is critically dependent on NF-kB signaling. He we are taking a broader view based on our published data applying mouse genetic tools and infectious disease model systems that identified and validate additional receptor signaling, signal transduction and transcriptional control pathways in phagocytic cells that are amenable to pharmacological manipulation to boost antibacterial capacities of macrophages and neutrophils. In Nature 2005, we found that mice lacking the IKKa kinase regulating NF-kB activation had increased inflammatory responses and bactercidal activity. In Aim 1, we will use in vivo and ex vivo studies the role of IKKa kinase in regulation of phagocyte bactericidal and inflammatory responses to MRSA and PA, and probe its relationship to HIF-1 mediated cellular energy metabolism. In Nature Immunology 2010, we discovered that mice lacking IKKP kinase regulating NFkB activation increased IL-ip/IL-1R signaling to boost neutrophil numbers and bacterial defense vs. GAS. In Aim 2 of the proposal, we will use ex vivo and in vivo models along with specific pharmacologic antagonists to evaluate the roles of IKKp kinase and downstream IL-ip/IL-1R signaling in regulation of phagocyte bactericidal and inflammatory responses to antibiotic-resistant bacterial pathogens. In Science 2006, we observed a role of A3 adenosine receptors in neutrophil chemotaxis, and in Aim 3 of the proposal we will study the role ofthe A3 receptor signaling in regulation of phagocyte bactericidal and inflammatory responses to MRSA and PA. In Immunity 2011, we found that P2X7 receptors mediate ATP detection and macrophage-mediated host defense against B. anthracis, and in Aim 4 we will probe the role of the ATP/P2X7 receptor signaling and inflammasome activation in regulation of phagocyte bactericidal and inflammatory responses