Modulation of Salmonella Infection by Focal Adhesion Kinase

粘着斑激酶对沙门氏菌感染的调节

基本信息

批准号：
7775043
负责人：
Katherine A. Owen
金额：
$ 5.05万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7775043
关键词：
Acute Affect Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotic Resistance Attenuated Bacteria Biological Models Bone Marrow Cells Cessation of life Complex Cultured Cells Data Dendritic Cells Disease Distal Epithelial Epithelial Cells Equilibrium Focal Adhesion Kinase 1 Focal Adhesions Gastroenteritis Genes Goals Health Host Defense Human Immune response Infection Infection Control Infiltration Inflammation Inflammatory Inflammatory disease of the intestine Integrins Interleukin-1 Interleukin-6 Interleukin-8 Intestines Investigation Knockout Mice Lamina Propria Liver Mediating Membrane Messenger RNA Modeling Mus Myelogenous Organism Pathogenesis Pathology Pattern Phagocytes Phase Play Population Predisposition Production Proteins Receptor Protein-Tyrosine Kinases Regulation Research Role Salmonella Salmonella infections Salmonella typhimurium Septicemia Severities Signal Pathway Signal Transduction Signaling Molecule Site Small Intestines Spleen Staging Techniques Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Typhoid Fever cell motility chemokine cytokine directional cell enteric pathogen human disease ileum in vivo intestinal epithelium knockout animal macrophage migration monocyte mouse model neutrophil pathogen research study resistant strain villin

项目摘要

DESCRIPTION (provided by applicant): Bacteria of the genus Salmonella are a group of gram-negative pathogens that cause a wide range of human diseases from localized gastroenteritis to typhoid fever and septicemia. Although significant progress has been made in understanding the mechanisms of Salmonella pathogenesis, more than 12 million cases of typhoid fever occur annually, and emerging antibiotic resistant strains pose a significant threat to human health. The overall goal of the proposed research is to understand how the non-receptor tyrosine kinase Focal Adhesion Kinase (FAK) functions in host defense against the enteric pathogen S. typhimurium. The experiments outlined herein provide an integrated approach to determine how this molecule affects Salmonella disease pathology through its impact on the innate immune response and the integrity of the intestinal epithelial barrier. In Specific Aim 1, we will determine how FAK expression by macrophages modulates the cellular immune response during Salmonella infection in vivo. We will accomplish this by examining bacterial colonization levels and inflammation in tissues derived from wildtype and myeloid-specific conditional FAK knockout mice. We will also examine the phagocytic capacity of FAK-deficient macrophages using advanced flow cytometric techniques. The studies described in this aim will elucidate how differences in the recruitment and/or function of phagocytes occurring in the absence of FAK impact the complex balance between host survival and death. While the presence of cytokines helps initiate and regulate the immune response to Salmonella, the appropriate balance between pro- and anti-inflammatory cytokines is essential to control infection and avoid damage to the host. In Specific Aim 2, we will investigate the FAK-mediated signaling pathways involved in macrophage-mediated cytokine production during Salmonella infection. To do this, we will first examine the ability of FAK-deficient macrophages to produce pro- and anti-inflammatory cytokines followed by an investigation into the specific signaling molecules involved in cytokine production. Finally, in Specific Aim 3, we will determine how FAK expression in the intestinal epithelium impacts host susceptibility to Salmonella infection. Using mice in which FAK is conditionally deleted from the intestinal epithelium, we will assess how the loss of this molecule from the epithelial barrier affects bacterial colonization levels in the small intestine and dissemination to distal tissues.

描述（由申请人提供）：沙门氏菌属的细菌是一组革兰氏阴性病原体，引起了从局部胃炎到伤寒和败血症的广泛人类疾病。尽管在理解沙门氏菌发病机理的机制方面取得了重大进展，但每年发生超过1200万例伤寒病例，而新兴的抗生素抗药性菌株对人类健康构成了重大威胁。拟议的研究的总体目标是了解非受体酪氨酸激酶局灶性粘附激酶（FAK）如何在宿主防御中针对肠病原体S.鼠伤寒沙门氏菌的功能。本文概述的实验提供了一种综合方法，以确定该分子如何通过对先天性免疫反应和肠上皮屏障的完整性的影响来影响沙门氏菌病理学。在特定目标1中，我们将确定巨噬细胞的FAK表达如何调节体内沙门氏菌感染期间的细胞免疫反应。我们将通过检查源自野生型和髓样特异性有条件FAK敲除小鼠的组织中细菌定植水平和炎症来实现这一目标。我们还将使用先进的流式细胞仪技术检查FAK缺陷巨噬细胞的吞噬能力。在此目标中描述的研究将阐明在没有FAK的情况下发生的吞噬细胞募集和/或功能的差异如何影响宿主存活与死亡之间的复杂平衡。虽然细胞因子的存在有助于引发和调节对沙门氏菌的免疫反应，但促和抗炎细胞因子之间的适当平衡对于控制感染并避免损坏宿主至关重要。在特定的目标2中，我们将研究在沙门氏菌感染过程中涉及大噬细胞介导的细胞因子产生的FAK介导的信号传导途径。为此，我们将首先研究FAK缺陷巨噬细胞产生促和抗炎细胞因子的能力，然后研究参与细胞因子产生的特定信号分子。最后，在特定的目标3中，我们将确定肠上皮表达如何影响宿主对沙门氏菌感染的敏感性。使用从肠上皮有条件地删除FAK的小鼠，我们将评估该分子在上皮屏障中的损失如何影响小肠和远端组织中的细菌定植水平。