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，其特点是一种流行病，对代表性不足的少数族裔和儿童造成不成比例的影响。哮喘的下呼吸道炎症特征的常见来源是由常见环境过敏原引发的 Th2 介导的反应。多项关于哮喘的独立全基因组关联研究 (GWAS) 已确定，不同种族/种族群体中与哮喘最一致的相关基因。然而，IL-33/ST2 在调节哮喘先天适应性免疫相互作用中的生物学作用和机制仍有待确定。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，与哮喘发病机制存在新的联系。自噬参与将潜在的细胞质抗原递送至内体，供 DC 降解、加工、激活和呈递；其活性在哮喘气道中增加。我们假设 IL-33/ST2 和自噬途径在哮喘和过敏性疾病中发挥着至关重要的作用，并且 IL-33/ST2 在 Th2 介导的过敏性气道炎症中通过自噬调节先天适应性免疫相互作用。我们已经完成了 ST2 的靶向重测序，以识别非洲血统人群中罕见变异以及 GWAS 平台上的单核苷酸多态性 (SNP) 未很好“标记”的常见变异。我们鉴定了一种新颖且常见的单倍型，可以确定可溶性 ST2 (sST2) 的血清水平，该单倍型由三个可能改变转录因子结合的启动子变体组成。哮喘 GWAS 数据库的计算机分析确定了 84 个选定的关键自噬途径基因中的 11 个，这些基因的变异与非裔美国人的哮喘风险显着相关，表明该途径的变异可能普遍导致哮喘风险。在这项新申请的母 R01 资助中，我们几乎完成了超过 1,000 个哮喘病例和非哮喘对照的全基因组测序，这些对照由“美洲非洲裔人群哮喘联盟”(CAAPA) 组成。由此产生的超过 1,000 名患有哮喘的非洲血统个体的独特遗传变异目录为识别 IL-33/ST2 和自噬途径中的常见和罕见变异提供了独特的机会。本申请的具体目标是： (i) 鉴定与哮喘相关的 84 个自噬途径基因中的罕见和常见变异； (ii) 测试 IL-33/ST2 介导的自噬流作为树突状细胞稳态的关键决定因素，以及 IL-33/ST2 调节哮喘患者和非哮喘对照（每组 N=20）中先天适应性免疫相互作用的机制。这些研究的结果将有助于深入了解哮喘的发病机制、遗传基础和种族差异，以及临床治疗的新靶点。