Inducible Renitence in Macrophages

巨噬细胞中的诱导性记忆

基本信息

批准号：
9060953
负责人：
JOEL A SWANSON
金额：
$ 29.45万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9060953
关键词：
Address Asbestos Atherosclerosis Autophagocytosis Bacteria Bacterial Infections Calcium Cell physiology Cells Cholesterol Chronic Crohn&apos s disease Cytoplasm Disease Event Experimental Models Exposure to Genes Goals Health Human Immunocompromised Host Individual Infection Inflammation Inflammatory Interferons Investigation Kinetics Left Lipopolysaccharides Listeria Listeria monocytogenes Lysosomes Macrophage Activation Macrophage Cell Biology Measures Mechanics Membrane Methods Microbe Molecular Mus Mycoses Natural Immunity Nitrogen Parasitic infection Particulate Patients Phagocytes Phagolysosome Process Property Proteins Quantitative Evaluations Regulation Research Resistance Resistance to infection Role Silicon Dioxide Stimulus System TNF gene Testing Therapeutic Tissues Urea Vacuole Virulence Virus Diseases Work Wound Healing acid sphingomyelinase antimicrobial bacterial resistance base cytokine design in vitro Model inhibitor/antagonist lysosome membrane macrophage microbicide nanoparticulate novel pathogen pressure reactive oxygen intermediate repaired resistance mechanism synaptotagmin VII therapy design

项目摘要

DESCRIPTION (provided by applicant): Macrophages are essential to innate immunity to infections. Activation of macrophages by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) increases their microbicidal activities but also increases damage to tissues due to inflammation. As therapies which target chronic inflammation leave patients vulnerable to infections, new strategies are needed that can selectively increase macrophage antimicrobial activities. The long-term goal of this research is to devise such strategies through investigations of fundamental macrophage cell biology. This lab discovered recently that exposure of murine macrophages to bacteria, LPS, IFNγ or TNFα leads to stabilization of their lysosomes against mechanical damage, a phenomenon termed "inducible renitence" or IR. As vacuolar membrane damage is essential to the virulence of many pathogenic microbes, to infection by viruses and to inflammation by micro-articulates, this novel phenomenon could potentially be exploited therapeutically. The objective of the present work is to define the cellular and molecular basis of inducible renitence. The central hypothesis is that renitence is induced by classical activation and consists of enhanced mechanisms of membrane damage-repair. The experimental model for these studies is a system in which macrophage lysosomes or phagolysosomes are subjected to controlled levels of physical perturbation, which allows quantitative evaluation of mechanisms that resist or repair damage. The central hypothesis will be tested by addressing three specific aims. The first aim will determine the conditions and factors which induce renitence in human and murine macrophages. Renitence will be measured in classically activated macrophages, alternatively activated (wound-healing) macrophages and regulatory macrophages, as well as macrophages treated with other agents. The second aim will determine the role of membrane damage-repair mechanisms in renitence. The kinetics of phagolysosome damage and repair will be measured and the contributions of vacuolar calcium, synaptotagmin VII and acid sphingomyelinase to renitence will be analyzed. The third aim will determine the role of renitence in macrophage resistance to infection by the Gram-positive intracellular pathogen Listeria monocytogenes, which normally scapes into cytoplasm by damaging vacuolar membranes. By defining the cellular and molecular basis of IR, this research will introduce a new strategy for manipulation of macrophage function. Therapies which increase renitence selectively could reduce inflammation due to micro-particulates or benefit immunosuppressed patients and individuals with chronic inflammatory diseases, such as therosclerosis and Crohn's disease.

描述（由申请人提供）：巨噬细胞对于感染的先天免疫至关重要。脂多糖（LPS）和细胞因子（例如干扰素-γ（IFNγ）和肿瘤坏死因子-α（TNFα））激活巨噬细胞会增加其杀菌活性。由于针对慢性炎症的治疗使患者容易受到感染，因此需要新的策略来选择性地增加巨噬细胞的抗菌能力。这项研究的长期目标是通过对基本巨噬细胞生物学的研究来制定此类策略。该实验室最近发现，小鼠巨噬细胞暴露于细菌、LPS、IFNγ 或 TNFα 可以使其溶酶体稳定，免受机械损伤。这种现象被称为“诱导性滞留”或 IR，因为液泡膜损伤对于许多病原微生物的毒力、病毒感染和炎症至关重要。微关节，这种新现象有可能在治疗上得到利用，目前工作的目的是定义诱导性滞留的细胞和分子基础，中心假设是滞留是由经典激活诱导的，并且由膜损伤的增强机制组成。这些研究的实验模型是一个系统，其中巨噬细胞溶酶体或吞噬溶酶体受到受控水平的物理扰动，从而可以定量评估抵抗或修复损伤的机制。将通过解决三个具体目标来测试假设。第一个目标将确定诱导人类和小鼠巨噬细胞的恢复的条件和因素。恢复将在经典激活的巨噬细胞、选择性激活的（伤口愈合）巨噬细胞和调节性巨噬细胞中进行测量。第二个目标是确定膜损伤修复机制在修复中的作用，并测量吞噬溶酶体损伤和修复的动力学及其贡献。第三个目标将分析液泡钙、突触结合蛋白 VII 和酸性鞘磷脂酶对滞留的作用，以确定滞留在巨噬细胞抵抗革兰氏阳性细胞内病原体单核细胞增生李斯特菌的感染中的作用，该病原体通常通过破坏液泡膜进入细胞质。该研究定义了 IR 的细胞和分子基础，将引入一种操纵巨噬细胞功能的新策略，以增加记忆力。选择性地可以减少微粒引起的炎症，或使免疫抑制患者和患有慢性炎症性疾病（如动脉粥样硬化和克罗恩病）的个体受益。