EPIGENETIC PROGRAMMING OF INNATE IMMUNITY IN PEDIATRIC AIRWAY EPITHELIUM

儿童气道上皮先天免疫的表观遗传编程

• 批准号: 9111857
• 负责人: Lisa A Miller
• 金额: $ 19.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111857
• 关键词: Adjuvant; Adult; Age; Alveolitis; Alveolus; Antibodies; Bronchiolitis; Cell Culture Techniques; Cells; Child; Childhood; Clinical; Data; Development; Environmental Exposure; Epigenetic Process; Epithelial Cells; Exploratory/Developmental Grant; Foundations; Future; Genetic Transcription; Goals; Health; Hematoxylin and Eosin Staining Method; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Host Defense; Human; Immune; Immune system; Immunity; Immunocompromised Host; In Vitro; Infant; Infection; Infectious Agent; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Leukocytes; Life; Link; Lung; Macaca mulatta; Measurement; Measures; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Monkeys; Mucosal Immunity; Natural Immunity; Neonatal; Nose; Pathway interactions; Pattern recognition receptor; Phenotype; Publishing; Regulation; Research; Respiratory Tract Infections; Role; School-Age Population; Staining method; Stains; Structure of respiratory bronchiole; Surface; Testing; Viral; Virus; Virus Diseases; adaptive immunity; airway epithelium; chromatin immunoprecipitation; clay; epigenome; histone modification; immunogenicity; in vivo; influenza virus vaccine; inhibitor/antagonist; innate immune function; innovation; interleukin-22; mucosal vaccine; nonhuman primate; pathogen; postnatal; predictive marker; programs; promoter; receptor; research study; response; transcriptome; transcriptome sequencing; vaccine efficacy

 DESCRIPTION (provided by applicant): The first year of human life is a period of significant maturation for both the lung and immune system. Infants are more susceptible to respiratory infections as compared to school age children and adults, but the immune mechanisms for this clinical observation are not well understood. The neonatal period of life is further challenged by reduced vaccine efficacy, which is in part due to developmental shifts in leukocyte function that limit establishment of protective immunity. It is currently unknown whether structural cells of the lung also contribute to the immunocompromised state of the infant. Of particular relevance is the role of the epithelial cell in conducting airways, which is architecturally and functionally poisedto serve as an innate immune liaison to the adaptive immune system. Given that mucosal surfaces serve as the first line of host defense, enhancement of innate immune function in airway epithelium may facilitate a more robust adaptive immune response towards infectious agents. The overall goal of our research is to understand the molecular mechanisms that program innate immune function in airway epithelial cells of the postnatal lung. In a pediatric model of H1N1 influenza infection, we have observed persistent bronchiolitis and alveolitis in infant rhesus monkey airways despite viral clearance. Infant monkey airway epithelial cell cultures revealed a modulated innate immune phenotype following H1N1 infection, as compared with adult monkey airway epithelial cell cultures. We now provide data demonstrating that interleukin 22 receptor, alpha 1 (IL-22R1), is developmentally regulated in infant monkey airway epithelial cells in a histone deacetylase dependent fashion. Given our published and preliminary findings, we hypothesize that limited host pathogen defense in the infant is mediated, in part, by modulated innate immune pathways in the airway epithelium. We further propose that the regulation of modulated innate immune pathways in infant airway epithelium is dependent upon epigenetic mechanisms. To test our hypothesis, we will use both in vitro and in vivo strategies in the context of H1N1 infection to (1) define the continuum of the infant airway epithelium transcriptome relative to adult airway epithelium in the context of viral infection; (2) investigat the epigenetic mechanisms that regulate IL-22R1 in the infant airway epithelium; (3) determine if epigenetic inhibitors can enhance mucosal immunity in infant airways. The rationale for proposing these exploratory studies under the R21 mechanism is to provide the foundation for the development of new adjuvant strategies for host defense directed at pediatric airway epithelium, by targeting specific molecules associated with innate immune pathways. While it is understood that airway epithelium has multiple pattern recognition receptors to recognize a diverse array of pathogens, here we will focus on influenza as a paradigm for respiratory infections.

 描述（通过应用程序提供）：人类生命的第一年是肺和免疫系统的重要成熟时期。与学龄儿童和成人相比，婴儿更容易受到呼吸道感染的影响，但是这种临床观察的免疫机制尚不清楚。疫苗效率降低，生命的新生儿时期进一步挑战，这部分是由于白细胞功能的变化限制了受保护的免疫力的建立。目前尚不清楚是否 肺也有助于婴儿的免疫功能低下。特别相关的是上皮细胞在进行气道中的作用，该气道被存档并在功能上有毒，可以作为适应性免疫系统的先天免疫联络。鉴于粘膜表面是宿主防御的第一线，因此，气道上皮中先天免疫功能的增强可能会促进对传染剂的更强大的适应性免疫反应。我们研究的总体目的是了解在产后肺的气道上皮细胞中编程先天免疫学功能的分子机制。在H1N1影响的儿科模型中，我们观察到婴儿恒河猴猴气道目的地病毒清除率的持续性支气管炎和肺泡炎。与成年猴子气道上皮细胞培养物相比，婴儿猴气道上皮细胞培养物显示出H1N1感染后的定型先天免疫学表型。现在，我们提供数据，证明白介素22受体Alpha 1（IL-22R1）以组蛋白脱乙酰基酶依赖性方式在婴儿猴气道上皮细胞中开发。鉴于我们发表的初步发现，我们假设婴儿中有限的宿主病原体防御是由气道上皮中的定型先天免疫途径介导的。婴儿气道上皮的途径取决于上皮机制。为了检验我们的假设，我们将在H1N1感染的背景下同时使用体外和体内策略，以（1）在病毒感染的背景下定义婴儿气道上皮转录组的连续体相对于成人气道上皮； （2）研究调节婴儿气道上皮中IL-22R1的表观遗传机制； （3）确定表观遗传抑制剂是否可以增强婴儿气道中的粘膜免疫呈现。根据R21机制提出这些探索性研究的基本原理是为针对针对小儿气道上皮的宿主防御的新调整策略提供基础，该策略是通过针对与先天性流经通道相关的特定分子的。虽然可以理解，气道上皮具有多种模式识别受体来识别一系列病原体，但在这里，我们将专注于有影响力的人作为呼吸道感染的范式。