Pathophysiology of Influenza A Virus-induced Lung Injury in Juveniles

甲型流感病毒引起的青少年肺损伤的病理生理学

基本信息

批准号：
10208942
负责人：
Bria M Coates
金额：
$ 16.12万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208942
关键词：
Acute Acute Lung Injury Adolescent Adult Adult Respiratory Distress Syndrome Age Alveolar Macrophages Animal Model Antibodies Antiviral Agents Antiviral Response Antiviral Therapy Automobile Driving CCL2 gene CCR1 gene Cell model Cells Cessation of life Child Childhood Childhood Injury Clinical Clinical Data Communication Coupled Critically ill children Data Data Analyses Development Disease Disease Progression Epidemic Epithelial Cells Equilibrium Experimental Designs Fostering Functional disorder Gene Expression Goals IRF3 gene ITGAX gene Immune response Immunologic Memory Impairment Infection Infection Control Inflammasome Inflammatory Inflammatory Response Influenza Influenza A virus Innate Immune Response Interferon-alpha Interferon-beta Interleukin-1 beta Interleukin-18 Intervention Knowledge Laboratory Procedures Life Lung Lung Inflammation Mediating Medical Mentors Morbidity - disease rate Mus Pathogenesis Pathway interactions Patients Peripheral Physicians Pneumonia Population Prevention Process Production Receptor Activation Receptor Signaling Regulation Research Respiratory Tract Infections Risk Role Scientist Signal Transduction Supportive care Testing Therapeutic Tissues Training Training Programs Translating Viral Viral Pneumonia Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Vulnerable Populations alveolar epithelium alveolar type II cell base cell type chemokine receptor clinically relevant comorbidity design gamma-Chemokines in vitro Model in vivo influenza infection laboratory experience lung development lung injury mature animal monocyte monocyte chemoattractant protein 1 receptor mortality mouse model novel novel therapeutics pandemic disease patient population pediatric patients prevent receptor receptor expression recruit response skills tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY The broad objectives of this K08 proposal are two-fold: (1) to foster the development of essential scientific and professional skills that will allow the candidate, Dr. Bria Coates, to achieve her long-term goal of becoming an independent physician-scientist concentrating on the development of acute lung injury in children with viral respiratory infections and seeking solutions that could be translated for therapeutic benefit to critically ill children, and (2) to investigate mechanisms that regulate the immune response to influenza A virus (IAV) and contribute to increased morbidity and mortality in the pediatric patient population. Through laboratory experience, didactic coursework, and the collaborative process, Dr. Coates will gain expertise in experimental design, laboratory procedures, data analysis, and scientific communication. Dr. Coates and her mentor, Dr. Karen Ridge, have designed a specific training plan that will afford Dr. Coates new knowledge and research skills in the pathophysiology of acute lung inflammation and acute respiratory distress syndrome (ARDS), which is a lung condition that causes tremendous morbidity and mortality in young patients with viral respiratory infections. Importantly, recent clinical data thwart the long-standing dogma that children with influenza have increased morbidity and mortality due to impaired viral clearance. Our preliminary data identify an altered innate immune response in IAV-infected juvenile mice as a critical parameter in disease progression. Specifically, we show that increased lung injury in IAV-infected juvenile mice is associated with robust activation of the NOD-like receptor (NLR) proteins NOD2 and the NLRP3, resulting in increased IFNα/β and IL-1β/18 levels, respectively, that persist beyond viral elimination. In addition, juvenile lungs produce more MCP-1 and recruit more inflammatory monocytes during IAV infection, which then perpetuates NOD2 and NLRP3 activation. We observe that juvenile recruited monocytes are uniquely inflammatory, and prevention of their recruitment during IAV infection protects juvenile mice from IAV-mediated lung injury. We hypothesize that age-specific, cell autonomous differences in the innate immune response to IAV contribute to the robust and sustained activation of NLR proteins and exacerbate IAV-induced lung injury in juvenile mice. We have formulated three interrelated specific aims to study the regulation of monocyte recruitment and NLR signaling in both in vivo and in vitro models of juvenile IAV-induced lung injury. Specific Aim 1: Investigate the age-specific mechanisms that modulate the activation of NLR proteins in response to IAV infection and contribute to IAV-induced acute lung injury. Specific Aim 2: Determine whether recruited monocytes are required for IAV-mediated acute lung injury in juvenile mice. Specific Aim 3: Identify cell autonomous differences in juvenile IAV infection that may drive age-specific inflammatory responses. Completion of these aims will provide a rigorous training program for Dr. Coates and uncover mechanisms driving acute lung injury in children with viral respiratory infections.

项目摘要该K08提案的广泛目标是两个方面：（1）促进基本科学和将允许候选人布里亚·科茨（Bria Coates）博士实现她的长期目标的专业技能独立的身体科学家专注于病毒儿童急性肺损伤的发展呼吸道感染和寻求可以转化的解决方案，以获得治疗益处的治疗益处儿童和（2）调查调节免疫激发以影响病毒（IAV）和有助于小儿患者人群的发病率和死亡率提高。通过实验室经验，教学课程和协作过程，科茨博士将获得实验方面的专业知识设计，实验室程序，数据分析和科学沟通。科茨博士及其导师博士凯伦·里奇（Karen Ridge）设计了一个特定的培训计划，该计划将负担科茨博士的新知识和研究急性肺注射和急性呼吸窘迫综合征（ARDS）病理生理学的技能，这是一种肺部疾病，会导致病毒的年轻患者引起巨大的发病率和死亡率呼吸道感染。重要的是，最近的临床数据阻止了儿童的长期教条由于病毒清除受损而导致的发病率和死亡率增加。我们的初步数据识别 IAV感染的少年小鼠的先天免疫响应改变是疾病的关键参数特别是，我们表明，IAV感染的少年小鼠的肺损伤增加与 NOD样受体（NLR）蛋白NOD2和NLRP3的强大激活，导致IFNα/β增加和IL-1β/18水平，分别持续超出病毒消除。此外，少年肺部产生更多 MCP-1并在IAV感染期间募集更多炎症单核细胞，然后将NOD2和 NLRP3激活。我们观察到少年招募的单核细胞是独特的炎症，并且预防他们在IAV感染期间的招募可保护少年小鼠免受IAV介导的肺损伤。我们假设对IAV的先天免疫反应中特定年龄的细胞自主差异有助于 NLR蛋白的强大而持续的激活和加剧IAV诱导的肺损伤老鼠。我们已经制定了三个相互关联的特定目的，以研究单核细胞募集的调节和幼年IAV诱导的肺损伤的体内和体外模型中的NLR信号传导。具体目标1：研究针对IAV的NLR蛋白调节活化的年龄特异性机制感染并导致IAV诱导的急性肺损伤。特定目标2：确定是否招募 IAV介导的幼体急性肺损伤需要单核细胞。特定目标3：识别单元格少年IAV感染的自主差异可能会导致年龄特异性炎症反应。这些目标的完成将为Coates博士提供严格的培训计划，并发现机制驱动病毒呼吸道感染儿童的急性肺损伤。