Inducible Renitence in Macrophages

巨噬细胞中的诱导性记忆

• 批准号: 8723245
• 负责人: JOEL A SWANSON
• 金额: $ 29.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8723245
• 关键词: Address; Asbestos; Atherosclerosis; Autophagocytosis; Bacteria; Bacterial Infections; Calcium; Cell physiology; Cells; Cholesterol; Chronic; Crohn' 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; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; 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; public health relevance; reactive oxygen intermediate; repaired; resistance mechanism; seal; synaptotagmin VII; therapy design

DESCRIPTION (provided by applicant): Macrophages are essential to innate immunity to infections. Activation of macrophages by lipopolysaccharide (LPS) and cytokines such as interferon-? (IFN?) and tumor necrosis factor-¿ (TNF¿) 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, IFN? or TNF¿ 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）：巨噬细胞对于脂多糖（LPS）和细胞因子（例如干扰素-α（IFN？）和肿瘤坏死因子-¿）的天然免疫作用至关重要。 (TNF¿) 增加了其杀菌活性，但也增加了炎症对组织的损害。由于针对慢性炎症的治疗使患者容易受到感染，因此需要能够选择性增加巨噬细胞抗菌活性的新策略。该实验室最近发现，小鼠巨噬细胞暴露于细菌、脂多糖、干扰素或肿瘤坏死因子，以制定此类策略。导致溶酶体稳定以抵抗机械损伤，这种现象被称为“诱导性保留”或IR。由于液泡膜损伤对于许多病原微生物的毒力、病毒感染和微关节炎症至关重要，因此这种新现象可能目前工作的目的是确定诱导性记忆的细胞和分子基础，核心假设是记忆是由经典激活和诱导的。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。通过解决三个具体目标进行测试，第一个目标将确定诱导人类和小鼠巨噬细胞恢复的条件和因素将在经典激活的巨噬细胞中测量恢复。 （伤口愈合）巨噬细胞和调节性巨噬细胞，以及用其他药物处理的巨噬细胞将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以及液泡的贡献。将分析钙、突触结合蛋白 VII 和酸性鞘磷脂酶对 renitence 的影响，第三个目标将确定 renitence 在巨噬细胞抵抗感染中的作用。革兰氏阳性细胞内病原体单核细胞增多性李斯特菌通常通过破坏液泡膜进入细胞质。通过定义 IR 的细胞和分子基础，这项研究将引入一种新的策略来操纵巨噬细胞功能，选择性地增加滞留，从而减少巨噬细胞的滞留。微颗粒引起的炎症或对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）的个体有益。