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
基本信息
- 批准号:8721683
- 负责人:
- 金额:$ 71.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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(由适用提供):哮喘影响全球估计有3亿人,这是基础科学对临床医学受益的重要挑战。最近,基因组广泛关联研究的两项独立的荟萃分析GWAS数据已将编码IL-1家族细胞因子IL-33及其接收器IL1RL1(ST2)的基因确定为哮喘的易感性。大量功能归因于IL-33,包括激活2型先天性淋巴样细胞,TH2细胞的扩展以及CD8 T细胞的抗病毒功能的增强。随着将IL-33与哮喘病因相关的细胞和分子机制成为严格审查的重点,几个基本问题仍然没有解决。该应用着重于在转录水平和有机水平上阐明人IL33表达的调节。虽然已知IL33在上皮细胞和结构细胞中始终表达,但我们和其他人最近发现了鼠造血细胞产生的IL-33。现在,我们证明IL33在人肺白细胞中表达,并且过敏原诱导人CD14+单核细胞中的IL33表达。这些发现表明,肺中IL33表达的新范式,并代表了一种创新的机会,可以理解这种细胞因子在气道Th2感染中的影响组织特异性表达。使用Encode和1000个基因组数据库,我们在对IL33基因座的调节表观遗传景观的计算机询问中进行了进行,并确定了两个高关注的区域。一个区域具有强大的增强剂活性,第二个区域包含两个定义的CTCF结合位点,暗示了绝缘体活性。现在,我们证明了第一个区域可以充当增强剂,重要的是,该活动是由专门在非洲血统中发现的SNP修改的。无论多么有用,这些公共数据库都无法强调调节元素,这些元素仅在通过环境刺激诱导基因表达后才能成为证据。这就是过敏原刺激后原代细胞中IL33表达的调节可能会阐明在静态细胞系中未实现的新型调节元件。我们研究的中心假设认为,调节元素内的非编码遗传变异改变了IL33的临时和空间表达模式,这是IL33基因座与哮喘风险的SNP相关性背后的核心机制。为了检验该假设,提出了以下目的:1)确定在刺激的造血细胞和支气管上皮细胞中IL33基因表达上发生的表观遗传变化。 2)确定角色
增强子元件在IL33表达的调节中发挥作用; 3)确定CTCF在IL33表达中的作用。
项目成果
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数据更新时间:2024-06-01
Marcelo A. Nobrega的其他基金
Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
- 批准号:1045377310453773
- 财政年份:2021
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
- 批准号:1026198710261987
- 财政年份:2021
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
Integrated genetic, omic, and immunologic studies to identify endotypes and novel drug targets for asthma and allergic diseases
综合遗传、组学和免疫学研究,以确定哮喘和过敏性疾病的内型和新药物靶点
- 批准号:1061577810615778
- 财政年份:2021
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
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:92472459247245
- 财政年份:2014
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
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:92811759281175
- 财政年份:2014
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
Dissecting of the Tbx20 Regulatory Network
剖析 Tbx20 监管网络
- 批准号:78513147851314
- 财政年份:2009
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
Dissecting of the Tbx20 Regulatory Network
剖析 Tbx20 监管网络
- 批准号:73734467373446
- 财政年份:2009
- 资助金额:$ 71.63万$ 71.63万
- 项目类别:
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