Integrin-dependent modulation of macrophage function

巨噬细胞功能的整合素依赖性调节

• 批准号: 9207062
• 负责人: Nelson Cesar Di Paolo
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207062
• 关键词: Ablation; Acute Disease; Adenoviruses; Adult; Adult Respiratory Distress Syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Biological Process; Blood; Blood-Borne Pathogens; CASP1 gene; Cell Death; Cells; Cessation of life; Chronic Disease; Clinical Trials; Coagulation Process; Complement Activation; Conduct Clinical Trials; Cues; Data; Dose; Embryo; Environment; Equilibrium; Exhibits; Extracellular Matrix; Francisella tularensis; Gene Delivery; Gene Transfer; Genetic Transcription; Goals; Hepatic artery; Heterogeneity; Hour; Human; IRF3 gene; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Innate Immune Response; Innate Immune System; Integrins; Interleukin-1 alpha; Intervention; Intravenous; Invaded; Kupffer Cells; Listeria monocytogenes; Liver; Macrophage Activation; Malignant Neoplasms; Molecular; Necrosis; Obesity; Organ failure; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phagocytes; Pharmacology; Phenotype; Policies; Population; Process; Research; Role; Sensory; Sepsis; Signal Pathway; Spleen; Sterility; Stress; Syndrome; System; Tissues; United States National Institutes of Health; Viral; Virulence Factors; base; cell type; extracellular; in vivo; insight; macrophage; monocyte; new therapeutic target; novel; particle; pathogen; phenotypic biomarker; programs; public health relevance; response; sensor; therapeutic target

 DESCRIPTION (provided by applicant): Tissue residential macrophages (Mφ) are the first line of defense and one of the key cellular compartments of the innate immune system with specialized sensory, homeostatic, and effector functions that enable host protection from invading pathogens and mount adequate response to tissue damage or stress. If homeostatic signaling pathways in Mφ become dis-regulated, tissue Mφ may contribute to pathology and it is currently believed that the vast majority of human acute and chronic diseases develop with significant contributions from pro-pathogenic factors derived from the Mφ compartment. Through analyzing transcriptional responses and necrotic cell death in vivo, we have made an original observation that despite the efficient trapping of viral and bacterial pathogens from the blood, resident Mφs in liver and spleen utilize distinct molecular machineries to execute necrosis and activate pro-inflammatory mediators. Furthermore, we serendipitously found that manipulation of β1 integrin expression on Mφ in vitro and in vivo drastically alters their anti-pathogen and pro-inflammatory response phenotypes. Because the phenotypic heterogeneity of tissue Mφs became evident only recently and now is a topic of intense research in the field, littl to no information is currently available on generalized molecular mechanisms that drive this heterogeneity both at phenotypic and functional levels. The major goals of this grant proposal are to evaluate the concept that integrins serve as sensors of extracellular cues and guide the functional commitment of Mφs to tissue microenvironments and to define the molecular mechanism and signaling pathway(s) that enable β1 integrin dependent functional specialization of Mφs that is critical for balanced homeostatic and/or protective host responses to viral and bacterial pathogens. Therefore, in Specific Aim 1, we will define molecular mechanisms and signaling pathways that enable β1 integrin-dependent modulation of pro-inflammatory Mφ responses in vitro. In Specific Aim 2, we will define the role of β1 integrin in guiding functiona specialization of liver and splenic Mφs in vivo. In Specific Aim 3, we will define the role of β1 integrin in guiding tissue commitment phenotypes of embryonically-derived and adult monocyte-derived Mφs in vivo. The proposed studies will provide new mechanistic insights into fundamental cellular and molecular biological processes related to pro- inflammatory Mφ responses in vivo, and will allow for identification of novel potential therapeutic targets to tame unwarranted severe and/or pathologic inflammation.

 描述（由申请人提供）：组织驻留巨噬细胞（Mφ）是第一道防线，也是先天免疫系统的关键细胞区室之一，具有专门的感觉、稳态和效应器功能，能够保护宿主免受入侵病原体的侵害，并对组织损伤或应激产生足够的反应。如果Mφ中的稳态信号通路变得失调，则组织Mφ可能有助于病理学，并且目前认为，绝大多数人类急性和慢性疾病的发展与来自Mφ隔室的促致病因子的显著贡献有关。通过分析体内转录反应和坏死细胞死亡，我们有了一个原始的观察，尽管从血液中有效地捕获病毒和细菌病原体，在肝脏和脾脏中的居民Mφ利用不同的分子机制来执行坏死和激活促炎介质。此外，我们意外地发现，在体外和体内操纵Mφ上的β1整合素表达显著改变了它们的抗病原体和促炎反应表型。由于组织Mφ的表型异质性直到最近才变得明显，并且现在是该领域的一个密集研究主题，因此目前几乎没有关于在表型和功能水平上驱动这种异质性的广义分子机制的信息。本基金申请的主要目标是评估整合素作为细胞外信号的传感器并指导Mφ对组织微环境的功能承诺的概念，并定义使M φ的β1整合素依赖性功能特化的分子机制和信号通路，这对于平衡稳态和/或保护宿主对病毒和细菌病原体的反应至关重要。因此，在特定目标1中，我们将定义体外促炎性Mφ反应的β1整合素依赖性调节的分子机制和信号通路。在具体目标2中，我们将明确β1整合素在体内引导肝和脾Mφ功能特化中的作用。在具体目标3中，我们将定义β1的作用 整合素在体内指导胚胎来源和成体单核细胞来源的Mφ的组织定型表型。这些研究将为了解体内与促炎性Mφ反应相关的基本细胞和分子生物学过程提供新的机制见解，并将允许鉴定新的潜在治疗靶点以驯服 不必要的严重和/或病理性炎症。