Functional Genomics of IL-33 expression and asthma risk

IL-33 表达和哮喘风险的功能基因组学

• 批准号: 9247245
• 负责人: Marcelo A. Nobrega
• 金额: $ 70.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247245
• 关键词: Affect; African; Alleles; Allergens; Asthma; Basic Science; Binding; Binding Sites; Biological Assay; CD14 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Clinical Medicine; Computer Simulation; Data; Databases; Elements; Enhancers; Epigenetic Process; Epithelial Cells; Etiology; Family; Gene Expression; Genes; Genetic Enhancer Element; Genetic Polymorphism; Genetic Transcription; Goals; Hematopoietic; Human; In Vitro; Individual; Inflammation; Interleukin-1; Leukocytes; Luciferases; Lung; Lung diseases; Lymphoid Cell; Mammalian Cell; Meta-Analysis; Molecular; Mus; Pattern; Play; Population; Positioning Attribute; Regulation; Regulatory Element; Risk; Role; Scanning; Suggestion; Susceptibility Gene; Testing; Th2 Cells; Tissues; Viral Physiology; Zebrafish; cytokine; functional genomics; gene induction; genetic variant; genome database; genome wide association study; genome-wide analysis; in vivo; innovation; interest; monocyte; novel; public health relevance; receptor

DESCRIPTION (provided by applicant): Asthma affects an estimated 300 million people worldwide and represents an important challenge for basic science to benefit clinical medicine. Recently, two independent meta-analysis of genome wide association studies GWAS data have identified the genes encoding the IL-1� family cytokine, IL-33, and its receptor, IL1RL1 (ST2), as susceptibility loci for asthma. A plethora of functions have been attributed to IL-33 including activation of type-2 innate lymphoid cells, expansion of Th2 cells, and augmentation of anti-viral function of CD8 T cells. As the cellular and molecular mechanisms connecting IL-33 to asthma etiology become the focus of intense scrutiny, several basic questions remain unanswered. This application focuses on elucidating the regulation of human IL33 expression, both at the transcriptional level as well as the organismal level. While IL33 is known to be constitutively expressed in epithelial cells and structural cells, we and others have recently found IL-33 produced by murine hematopoietic cells. We now demonstrate that IL33 is expressed in human lung leukocytes and that allergens induce IL33 expression in human CD14+ monocytes. These findings suggest a new paradigm of IL33 expression in the lungs, and represent an innovative opportunity to understand the impact tissue specific expression of this cytokine in airway Th2 inflammation. Using ENCODE and 1000 Genomes databases, we have performed in silico interrogation of the regulatory epigenetic landscape of the IL33 locus and have identified two regions of high interest; one region has strong enhancer activity, and a second region contains two defined CTCF binding sites, suggestive of insulator activity. We now demonstrate that the first region can function as an enhancer, and importantly, this activity is modified by a SNP found specifically in individuals of African ancestry. However useful, these public databases fail to highlight regulatory elements that only become evident after induction of gene expression by environmental stimulation. Thus, regulation of IL33 expression in primary cells after allergen stimulation will likely elucidate novel regulatory elements not realized in static cell lines. The central hypothesis of our study posits that noncoding genetic variants within regulatory elements alter the temporal and spatial expression patterns of IL33, and that this is a central mechanism behind the association of SNPs at the IL33 locus with asthma risk. To test this hypothesis the following aims are proposed: 1) identify the epigenetic changes that occur upon IL33 gene expression in stimulated hematopoietic cells and bronchial epithelial cells.; 2) determine the role the enhancer element(s) play in the regulation of IL33 expression; and 3) determine the role of CTCF in IL33 expression.

描述（由申请人提供）：哮喘在全球范围内估计有3亿美元的抑制作用，对基本E受益的重要挑战是对基因组广泛研究的两个独立的荟萃分析，GWAS数据已识别出IL-1。家族， IL-33及其受体IL1RL1（ST2）作为哮喘的易感基因座。审查的几个基本问​​题仍未得到答复，这是在转录水平上阐明人类IL33表达的调节IL-33造成造血细胞。在Airway th2中，我们在IL33基因座的调节景观中进行了1000个基因组数据。坐着，我们现在证明了第一个区域可以增强的绝缘体活动，重要的是，这种活动是由非洲血统中的SNP修改的。环境刺激33表达表达表达刺激性过敏原刺激的诱导基因表达可能会在静态细胞系中进行调节元素。这是一种中心机制，因为SNP在ILE中的缔合。提出了以下目的：1）在刺激的造血细胞和支气管上皮细胞中确定IL33基因表达上发生的表观遗传变化。 在IL33表达的调节中，增强子元件播放