Macrophage and monocyte TBK1 function in host defense against influenza

巨噬细胞和单核细胞 TBK1 在宿主防御流感中发挥作用

• 批准号: 9910442
• 负责人: Robert Stewart Hagan
• 金额: $ 17.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910442
• 关键词: Adaptor Signaling Protein; Adult; Adult Respiratory Distress Syndrome; Antigen-Antibody Complex; Antiviral Agents; Award; B-Lymphocytes; Basic Science; Biochemical; Blood; Bone Marrow; Cell Line; Cells; Cessation of life; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Complex; Data; Dendritic Cells; Development; Disease; Equilibrium; Genetic Transcription; Goals; Host Defense; Host Defense Mechanism; Human; Immune response; Immune signaling; Immunity; Immunology; Immunophenotyping; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Influenza; Innate Immune Response; Innate Immune System; Instruction; Intensive Care Units; Interferons; Knockout Mice; Learning; Lung; Lung infections; Malignant Neoplasms; Medical; Mentors; Metabolic syndrome; Molecular; Morbidity - disease rate; Mus; Myelogenous; Natural Immunity; Organ; Pathogenesis; Pathology; Pathway interactions; Patient-Focused Outcomes; Pattern recognition receptor; Pharmaceutical Preparations; Phosphotransferases; Physicians; Process; Proteins; Proteomics; Publishing; Regulation; Research; Resolution; Respiratory Tract Infections; Role; Scientist; Signal Pathway; Signal Transduction; Speed; Stream; T-Lymphocyte; TANK-binding kinase 1; Techniques; Testing; Therapeutic; Training; Translations; United States; Viral; Viremia; Virus; Virus Diseases; Virus Replication; Work; career; career development; cell type; chemokine; clinical practice; defined contribution; design; druggable target; experience; gene product; healing; improved; in vivo; inflammatory lung disease; influenzavirus; inhibitor/antagonist; lung injury; macrophage; microbial; monocyte; mortality; mouse model; novel; pathogen; preclinical development; preservation; prevent; programs; recruit; respiratory virus; response; seasonal influenza; skills; small molecule inhibitor; therapeutic target; tool; trafficking; transcriptomics

Project Summary The objective of this K08 Mentored Clinical Scientist Career Award Application is to facilitate development of essential skills that will allow the candidate to become an academic physician-scientist. The candidate and his mentor have designed a training plan that will include a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. Through coursework and practical experience, the candidate will develop a deeper understanding of the complex immune mechanisms that underlie influenza pathogenesis and the host immune response to infection. Through his continued clinical work in the medical intensive care unit, the candidate will have the opportunity to inform his basic research program as well as guide the translation of that work to clinical studies and practice. Influenza and other respiratory viruses cause thousands of cases of Acute Respiratory Distress Syndrome (ARDS) yearly in the United States alone and are a substantial driver of morbidity and mortality worldwide. Despite the availability of antiviral medications for influenza, there remains an urgent need for host- directed therapeutics that limit organ damage and can be deployed in a variety of viral illnesses. The initial response to viral infection centers on the innate immune system including type 1 interferon (IFN) expression from infected cells and responding cells such as macrophages and monocytes. Multiple viral and inflammatory inputs converge on signaling kinases such as TANK-binding kinase 1 (TBK1), and these proteins regulate immunity and inflammation in a highly cell type-specific manner. The function of TBK1 in promoting immunity apart from type 1 IFN expression remains highly undefined. The candidate's data demonstrate that TBK1 function in macrophages and monocytes promote accumulation of inflammatory macrophages in the lung, and that deleting myeloid TBK1 lessens host morbidity while preserving viral control. This novel finding of TBK1 function in macrophages points to the TBK1 axis as a possible druggable target in inflammatory lung disease. This proposal defines the contribution of TBK1 to monocyte- and macrophage-driven inflammation in lung infections with the goal of identifying actionable mechanisms that can be manipulated for host-directed therapeutics. The specific aims will utilize in vivo and in vitro techniques to study monocyte and macrophage function and the molecular aspects of innate immune signaling. In Aim 1, we will determine which monocyte subtype and macrophage subpopulation require TBK1 to enter the lung in influenza infection and examine the transcriptomic consequences of TBK1 function. In Aim 2, we will use mouse models to determine the upstream signals that activate macrophage TBK1 in influenza infection. Finally, in Aim 3 we will use biochemical and proteomic tools to examine the signaling consequences of virus- and chemokine-driven TBK1 activation in monocytes and macrophages. These studies will explore new observations concerning TBK1 function with the ultimate goal of improving patient outcomes in this frequently fatal disease.

项目概要 K08 指导临床科学家职业奖申请的目的是促进以下领域的发展： 使候选人成为一名学术医师科学家的基本技能。候选人和他的 导师设计了一个培训计划，其中包括严格的研究部分和教学 指导建立成功职业发展所需的思维过程和原则。 通过课程作业和实践经验，候选人将对 流感发病机制和宿主免疫反应背后的复杂免疫机制 感染。通过在医疗重症监护病房继续进行临床工作，候选人将拥有 有机会告知他的基础研究计划并指导该工作转化为临床研究 并练习。流感和其他呼吸道病毒导致数千例急性呼吸窘迫病例 仅在美国每年都会出现急性呼吸窘迫综合征 (ARDS)，并且是发病率和死亡率的重要驱动因素 全世界。尽管有治疗流感的抗病毒药物，但仍然迫切需要宿主 限制器官损伤的定向疗法，可用于多种病毒性疾病。最初的 对病毒感染的反应集中于先天免疫系统，包括 1 型干扰素 (IFN) 的表达 来自受感染的细胞和反应细胞，例如巨噬细胞和单核细胞。多种病毒和炎症 输入集中在信号激酶上，例如 TANK 结合激酶 1 (TBK1)，这些蛋白质调节 以高度细胞类型特异性的方式产生免疫和炎症。 TBK1促进免疫力的作用 除 1 型干扰素外，IFN 的表达仍然高度不确定。候选人的数据表明 TBK1 巨噬细胞和单核细胞的功能促进肺部炎症巨噬细胞的积累，以及 删除髓系 TBK1 可以降低宿主发病率，同时保持病毒控制。 TBK1 的这一新颖发现 巨噬细胞的功能表明 TBK1 轴可能是炎症性肺病的药物靶标。 该提案定义了 TBK1 对单核细胞和巨噬细胞驱动的肺部炎症的贡献 感染的目标是确定可操作的可操作机制以用于宿主定向 疗法。具体目标将利用体内和体外技术来研究单核细胞和巨噬细胞 先天免疫信号的功能和分子方面。在目标 1 中，我们将确定哪个单核细胞 亚型和巨噬细胞亚群在流感感染中需要TBK1进入肺部并检查 TBK1 功能的转录组结果。在目标 2 中，我们将使用鼠标模型来确定上游 流感感染中激活巨噬细胞 TBK1 的信号。最后，在目标 3 中，我们将使用生化和 蛋白质组学工具用于检查病毒和趋化因子驱动的 TBK1 激活的信号后果 单核细胞和巨噬细胞。这些研究将探索有关 TBK1 功能的新观察结果 最终目标是改善这种常见致命疾病的患者预后。