Inducible Renitence in Macrophages

巨噬细胞中的诱导性记忆

• 批准号: 8852635
• 负责人: JOEL A SWANSON
• 金额: $ 29.47万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852635
• 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; 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（由适用提供）：巨噬细胞对于先天免疫学至关重要。脂多糖（LPS）和细胞因子（例如干扰素）激活巨噬细胞？ （IFN？）和肿瘤坏死因子 - （TNF。）增加了其微生物活性，但由于炎症而增加了对组织的损害。由于靶向慢性感染的疗法使患者容易受到感染的影响，因此需要新的策略来选择性地增加巨噬细胞抗菌活性。这项研究的长期目标是通过研究基本巨噬细胞生物学来制定此类策略。该实验室最近发现，鼠巨噬细胞暴露于细菌，LPS，IFN？或TNF导致其溶酶体对机械损伤的稳定，这一现象称为“诱导恢复”或IR。由于真空膜损伤对于许多致病性微生物的病毒，病毒感染和通过微广告的炎症至关重要，因此可以潜在地探索这种新型现象。本工作的目的是定义可诱导肾上腺素的细胞和分子基础。中心假设是恢复原则是由经典激活引起的，并由增强的膜损伤修复机制组成。这些研究的实验模型是一个系统，在该系统中，巨噬细胞溶酶体或吞噬物体受控的物理扰动水平，可以定量评估抵抗或修复损害的机制。中心假设将通过解决三个特定目标来检验。第一个目的将确定诱导人和鼠巨噬细胞重生的条件和因素。将在经典活化的巨噬细胞，替代激活（伤口）巨噬细胞和调节性巨噬细胞以及与其他药物处理的巨噬细胞中测量的恢复率。第二个目标将决定膜损伤修复机制在重生中的作用。将测量吞噬体损伤和修复的动力学，并将分析真空钙，突触素蛋白VII和酸性鞘氨质酶对固定的贡献。第三个目的将决定革兰氏阳性细胞内病原体单核细胞增生的巨噬细胞耐药性在巨噬细胞耐药性中的作用，通常通过损害真空膜而造成细胞质现场。通过定义IR的细胞和分子基础，这项研究将引入一种操纵巨噬细胞功能的新策略。选择性提高肾上腺素的疗法可以减少由于微分或受益于免疫抑制的患者和患有慢性炎症性疾病的人，例如治疗性炎症和克罗恩病。