Elucidating the roles of alveolar macrophage inflammation and selfrenewal during influenza infection

阐明流感感染期间肺泡巨噬细胞炎症和自我更新的作用

• 批准号: 10063352
• 负责人: Jie Sun
• 金额: $ 45.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10063352
• 关键词: Aging; Alveolar Macrophages; Binding; Cessation of life; Complex; Defect; Development; Disease; Elderly; Exhibits; Functional disorder; Future; Genes; Genetic; Glycolysis; Homeostasis; Immune response; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Influenza A virus; Injury; Ligands; Lower Respiratory Tract Infection; Lung; Lung diseases; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Myeloid Cells; Names; Natural Immunity; Natural regeneration; Parabiosis; Pathway interactions; Pharmacology; Population; Preventive; Production; Pulmonary Inflammation; Recovery; Role; Signal Transduction; TCF7L2 gene; Techniques; Therapeutic; Tissues; Virus Diseases; aged; aging population; anti-influenza; antiviral immunity; beta catenin; cancer cell; global health; hypoxia inducible factor 1; in vitro activity; in vivo; influenzavirus; lung repair; macrophage; monocyte; novel; protein complex; response; self-renewal; stem; stem cell proliferation; tissue repair

Summary/Abstract Influenza A virus (IAV) constitutes an ongoing threat to global health. IAV infection is especially problematic in aged individuals, with estimated close to 90% IAV-associated deaths occurring in the elderly. Alveolar macrophages (AMs) are the primary lung macrophage population that are important in lung homeostasis, anti-viral immunity and tissue recovery. AMs exhibit stem-like features of self-renewal, but also can rapidly produce pro-inflammatory mediators upon stimulation, which could potentially contribute to pulmonary inflammation and injury during IAV infection. Little is known currently about the mechanisms modulating AM proliferative and inflammatory fate decisions in vivo, and the subsequent effects on tissue inflammation and recovery following IAV infection. In this application, we hypothesize that the interplay of b-catenin, HIF1-a and TCF-4 modulates AM self-renewal and inflammatory activity, thereby regulating pulmonary inflammation and tissue repair during IAV infection. Furthermore, we hypothesize that exaggerated b- catenin-HIF1-a expression dictates the aging-associated defects in AM self-renewal and function, thereby leading to severe pulmonary diseases and/or defective lung repair following IAV infection in aged hosts. Three specific Aims are proposed. Aim 1: To elucidate the associated-mechanisms by which b- catenin/HIF1-a complex modulates AM inflammatory activity and self-renewal, and subsequent effects on host diseases and recovery from IAV infection. Aim 2: To define the underlying mechanisms by which TCF- 4 regulates AM development, self-renewal and/or inflammation during homeostasis and following IAV infection. Aim 3: To determine the roles of dysregulated AM b-catenin/HIF1-a axis in contributing to aging- associated defects in AM function and regeneration, thereby causing severe IAV-associated diseases in aged hosts.

摘要/摘要 甲型流感病毒（IAV）对全球健康构成持续威胁。 IAV 感染尤其成问题 据估计，近 90% 的 IAV 相关死亡发生在老年人中。肺泡 巨噬细胞（AM）是主要的肺巨噬细胞群，对肺稳态很重要， 抗病毒免疫和组织恢复。 AMs 表现出类似茎的自我更新特征，而且可以快速 受到刺激后产生促炎介质，这可能有助于肺部 IAV 感染期间的炎症和损伤。目前对 AM 的调节机制知之甚少 体内增殖和炎症命运的决定，以及随后对组织炎症和炎症的影响 IAV 感染后的恢复。在此应用中，我们假设 b-连环蛋白、HIF1-a 的相互作用 TCF-4 调节 AM 自我更新和炎症活性，从而调节肺 IAV 感染期间的炎症和组织修复。此外，我们假设夸大了 b- 连环蛋白-HIF1-a 表达决定了 AM 自我更新和功能中与衰老相关的缺陷，从而 老年宿主感染 IAV 后会导致严重的肺部疾病和/或肺部修复缺陷。 提出了三个具体目标。目标 1：阐明 b- 的相关机制 连环蛋白/HIF1-a 复合物调节 AM 炎症活动和自我更新，以及随后对 宿主疾病和 IAV 感染的恢复。目标 2：定义 TCF 的基本机制 4 在稳态期间和 IAV 之后调节 AM 发育、自我更新和/或炎症 感染。目标 3：确定失调的 AM b-catenin/HIF1-a 轴在衰老过程中的作用 AM 功能和再生的相关缺陷，从而导致严重的 IAV 相关疾病 年迈的主人。