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: 8811919
• 负责人: Kathleen C Barnes
• 金额: $ 20.25万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811919
• 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; Health; 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; 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; rare variant; receptor; response; risk variant; targeted treatment; 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造成不成比例的影响。哮喘下呼吸道炎症的常见来源是由常见环境变应原引发的Th2介导的反应。关于哮喘的多个独立的全基因组关联研究(GWAS)已经确定，在不同的民族/种族群体中，与哮喘的关联最一致的基因。然而，IL-33/ST2在哮喘天然免疫-获得性免疫相互作用中的生物学作用和机制尚不清楚。最近的证据表明，IL-33激活的树突状细胞(DC)在Th2介导的过敏性气道炎症中起关键作用。此外，自噬是促进细胞内稳态的核心细胞过程，与哮喘的发病机制有新的联系。自噬参与将潜在的细胞质抗原运送到内体，由DC降解、处理、激活和呈递；在哮喘呼吸道中，自噬的活性增加。我们推测IL-33/ST2和自噬通路在哮喘和过敏性疾病中都起着重要作用，IL-33/ST2通过自噬在Th2介导的过敏性呼吸道炎症中调节先天适应性免疫相互作用。我们已经完成了ST2的有针对性的重测序，以识别非洲血统人群中罕见的变异以及没有被GWA平台上的单核苷酸多态(SNPs)很好地“标记”的常见变异。我们确定了一种新的和常见的单倍型，它决定了血清中可溶性ST2(Sst2)的水平，它由三个可能改变转录因子结合的启动子变体组成。在对哮喘的电子分析中，Gwas数据库确定了84个选定的关键自噬途径基因中的11个，其变异与非裔美国人的哮喘风险显著相关，这表明该途径的变异可能普遍导致哮喘风险。在对这一新应用的母公司R01拨款中，我们几乎完成了对1,000例哮喘病例和非哮喘对照的全基因组测序，组成了“美洲非洲裔人口哮喘联合会”(CAAPA)。由此产生的1,000名非洲血统哮喘患者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。这项应用的具体目的是：(I)识别与哮喘相关的84个自噬途径基因中罕见和常见的变异；以及(Ii)检测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调节哮喘患者和非哮喘对照组(每组20人)天然适应性免疫相互作用的机制。这些研究的结果将为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提供依据。

项目成果

Lysosome and Cytoskeleton Pathways Are Robustly Enriched in the Blood of Septic Patients: A Meta-Analysis of Transcriptomic Data.

溶酶体和细胞骨架途径在化脓性患者的血液中富含：转录组数据的荟萃分析。

• DOI: 10.1155/2015/984825
• 发表时间: 2015
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Ma J;Chen C;Barth AS;Cheadle C;Guan X;Gao L
• 通讯作者: Gao L