The autophagic pathway and atopic asthma: role of IL-33 and ST2

自噬途径和特应性哮喘：IL-33 和 ST2 的作用

• 批准号: 8677159
• 负责人: Kathleen C Barnes
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677159
• 关键词: Affect; African; African American; Allergens; Allergic Disease; Americas; Antibodies; Antigen-Presenting Cells; Antigens; Asthma; Autophagocytosis; Binding; Biological; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cataloging; Catalogs; Cell physiology; Characteristics; Child; Chronic Obstructive Airway Disease; Clinic; Communities; Computer Simulation; Cystic Fibrosis; Data; Data Set; Databases; Dendritic Cells; Disease; Endosomes; Epidemic; Epithelial Cells; Ethnic group; Extrinsic asthma; Family; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Grant; Haplotypes; Homeostasis; IgE; Immune response; Immune system; Individual; Inflammation; Interleukin-1; Interleukins; Lead; Ligands; Link; Lung diseases; Mediating; Meta-Analysis; Mexico; Parents; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Population Heterogeneity; Process; Production; Public Health; Publishing; Race; Reaction; Regulation; Research Infrastructure; Resources; Risk; Role; Sampling; Serum; Single Nucleotide Polymorphism; Source; T cell differentiation; T-Cell Activation; T-Lymphocyte; Targeted Resequencing; Testing; Th2 Cells; Time; Underrepresented Minority; Variant; adaptive immunity; airway inflammation; allergic airway inflammation; asthmatic airway; asthmatic patient; base; case control; cohort; cytokine; environmental allergen; genetic association; genome sequencing; genome wide association study; injured airway; insight; member; multidisciplinary; novel; novel therapeutic intervention; pathogen; programs; promoter; public health relevance; rare variant; receptor; response; risk variant; transcription factor; translational study

DESCRIPTION (provided by applicant): Asthma represents a major public health burden characterized as an epidemic that disproportionately affects underrepresented minorities and children. The usual source of the lower airway inflammation characteristic of asthma is a Th2-mediated reaction initiated by common environmental allergens. Multiple independent genome-wide association studies (GWAS) on asthma have identified, as the most consistently associated genes with asthma among diverse ethnic/racial groups. However, the biological role and mechanism of IL-33/ST2 in modulating the innate-adaptive immunity interaction in asthma remains to be defined. Recent evidence suggests that IL-33-activated dendritic cells (DCs) are critical for Th2- mediated allergic airway inflammation. Moreover, autophagy is a core cellular process that contributes to cellular homeostasis with emerging links to the pathogenesis of asthma. Autophagy is involved in the delivery of potential cytoplasmic antigens to the endosome for degradation, processing, activation and presentation by DCs; and its activity is increased in asthmatic airways. We hypothesize that both the IL-33/ST2 and autophagic pathways play a crucial role in asthma and allergic diseases and IL-33/ST2 modulates the innate-adaptive immunity interaction via autophagy in Th2-mediated allergic airway inflammation. We have completed targeted resequencing of ST2 to identify rare variants as well as common variation that is not well "tagged" by the single nucleotide polymorphisms (SNPs) on the GWAS platforms in populations of African ancestry. We identified a novel and common haplotype that determines serum levels of soluble ST2 (sST2), which is comprised of three promoter variants that potentially alter transcription factor binding. In silico analyses of asthma GWAS databases identify 11 out of 84 selected key autophagic pathway genes for which variants are significantly associated with risk of asthma in African Americans, suggesting variation in this pathway may universally contribute to asthma risk. In the parent R01 grant to this new application, we have nearly completed whole-genome sequencing of >1,000 asthma cases and non-asthmatic controls comprising the 'Consortium on Asthma among African-ancestry Populations in the Americas' (CAAPA). The resulting unique catalog of genetic variation in >1,000 individuals of African ancestry selected for asthma provides a unique opportunity to identify common and rare variants in the IL-33/ST2 and autophagic pathways. Specific aims of this application are: (i) To identify rare and common variants in 84 autophagic pathway genes associated with asthma; and (ii) To test IL-33/ST2-mediated autophagic flux as a critical determinant of dendritic cell homeostasis and the mechanisms by which IL-33/ST2 regulates the innate-adaptive immunity interaction in asthmatic patients and non-asthmatic controls (N=20 each group). Results from these studies will provide insight into the pathogenesis, the genetic underpinnings and ethnic disparities of asthma as well as novel targets for therapy in the clinic.

描述（由申请人提供）：哮喘是一种主要的公共卫生负担，其特征是一种流行病，对代表性不足的少数群体和儿童的影响不成比例。哮喘的下气道炎症特征的通常来源是由常见环境过敏原引发的Th2介导的反应。哮喘的多个独立全基因组关联研究（GWAS）已确定为在不同种族/种族群体中与哮喘最持续相关的基因。但是，IL-33/ST2在调节哮喘中先天自适应免疫相互作用中的生物学作用和机制尚待定义。最近的证据表明，IL-33激活的树突状细胞（DC）对于Th2介导的过敏性气道炎症至关重要。此外，自噬是一种核心细胞过程，有助于细胞稳态，并与哮喘的发病机理有新兴联系。自噬参与将潜在的细胞质抗原传递到内体的降解，加工，激活和表现。哮喘气道中的活性增加。我们假设IL-33/ST2和自噬途径在哮喘和过敏性疾病中起着至关重要的作用，而IL-33/ST2在TH2介导的过敏性气道炎症中通过自噬调节了先天自适应的免疫相互作用。我们已经完成了针对ST2的靶向重新配置，以识别稀有变体和常见变异，这些变体在非洲血统人群中GWAS平台上的单核苷酸多态性（SNP）不太“标记”。我们确定了一种新颖且常见的单倍型，该单倍型决定了可溶性ST2（SST2）的血清水平，该型由三种可能改变转录因子结合的启动子变体组成。在对哮喘GWAS数据库的计算机分析中，在84个选定的关键自噬途径基因中有11个与非洲裔美国人的哮喘风险显着相关，这表明该途径的差异可能会对哮喘风险有所贡献。在该新应用程序的父级R01赠款中，我们几乎完成了> 1,000例哮喘病例和非心律对照的全基因组测序，其中包括美洲非洲官方人群中“哮喘联盟”（CAAPA）。在哮喘中选择的> 1,000个非洲血统中遗传变异的独特目录为识别IL-33/ST2和自噬途径中的常见和稀有变体提供了独特的机会。该应用的具体目的是：（i）确定与哮喘相关的84个自噬途径基因中的稀有和常见变体； （ii）测试IL-33/ST2介导的自噬通量作为树突状细胞稳态的关键决定因素，以及IL-33/ST2调节哮喘患者先天自适应免疫相互作用的机制（n = 20组）（n = 20）。这些研究的结果将洞悉哮喘的发病机理，遗传基础和种族差异以及诊所治疗的新靶标。