Regulation of human immune function by 17q21 asthma risk polymorphism

 描述（由申请人提供）：17 q21多态性是儿童哮喘发生的最强遗传风险之一。在高风险队列中，rs7216389 SNP处具有17 q21风险TT基因型的人在幼儿时因鼻病毒而喘息，在儿童后期哮喘患病率为90%。该位点的一个基因ORMDL 3通过转基因小鼠模型直接参与哮喘发病机制。内质网驻留ORMDL 3的两种已知功能，Serca 2b钙泵抑制和鞘脂合成抑制，也与哮喘有关。Serca 2b泵抑制和随后的钙紊乱导致称为“未折叠蛋白反应”（UPR）的潜在促炎应激反应。UPR与哮喘发病的关系尚不清楚。ORMDL 3还调节嗜酸性粒细胞中的钙依赖性功能。目前对ORMDL 3功能的了解主要来自鼠模型和转染的细胞系。目前尚不清楚17 q21多态性和ORMDL 3表达的改变如何在生理上调节人类免疫细胞功能。我们假设17 q21基因型调节鼻病毒诱导的内质网应激反应，从而免疫处理病毒。对于这个建议，我们有相对独特的机会研究ORMDL 3调节功能的基因型的人嗜酸性粒细胞和外周血单核细胞（PBMC）。研究PBMC中不同细胞类型的初步研究揭示了B细胞中ORMDL 3表达的最大17 q21基因型差异。ORMDL 3在人嗜酸性粒细胞中也非常高表达。因此，在目标1中，我们将确定17 q21多态性对B细胞UPR和抗病毒基因表达的影响，以响应鼻病毒刺激。该目标还将研究ORMDL 3的调节，以及ORMDL 3升高改变UPR/抗病毒基因表达的机制。在目标2中，我们将确定17 q21多态性对嗜酸性粒细胞钙依赖功能的影响。我们的初步数据有力地支持了在17 q21多态性人类免疫细胞中检测显著基因表达和嗜酸性粒细胞功能差异的能力。更深入地了解17 q21变异和相关ORMDL 3表达如何影响免疫功能可能阐明为什么具有风险多态性的儿童易患哮喘。

 DESCRIPTION (provided by applicant): 17q21 polymorphism is one of the strongest identified genetic risks for the development of childhood asthma. In a high risk cohort, those with the 17q21 risk TT genotype at the rs7216389 SNP who wheezed with rhinovirus as toddlers had a 90% prevalence of asthma later in childhood. One of the genes at that locus, ORMDL3, has been directly implicated in asthma pathogenesis by a transgenic mouse model. Both known functions of the endoplasmic reticulum resident ORMDL3, Serca2b calcium pump inhibition and sphingolipid synthesis inhibition, have also been implicated in asthma. Serca2b pump inhibition, and consequent calcium derangements, results in a potentially pro-inflammatory stress response known as the "Unfolded Protein Response" (UPR). The relationship between UPR and asthma pathogenesis is not clear. ORMDL3 also regulates calcium dependent functions in eosinophils. Current knowledge of ORMDL3 function derives primarily from murine models and transfected cell lines. It is not known how 17q21 polymorphisms and resulting alterations in ORMDL3 expression physiologically modulate human immune cell function. We hypothesize that 17q21 genotype regulates rhinovirus-induced ER stress responses and thus immune handling of the virus. For this proposal, we have the relatively unique opportunity of studying ORMDL3 regulated function in genotyped human eosinophils and peripheral blood mononuclear cells (PBMC). Preliminary studies investigating different cell types among PBMC revealed the greatest 17q21 genotypic differences for ORMDL3 expression in B cells. ORMDL3 was also very highly expressed in human eosinophils. Thus, in Aim 1 we will determine the effect of 17q21 polymorphism on B-cell UPR and anti-viral gene expression in response to rhinovirus stimulation. This aim will also investigate the regulation of ORMDL3, and the mechanisms by which elevated ORMDL3 alters UPR/anti-viral gene expression. In Aim 2, we will determine the consequences of 17q21 polymorphism for eosinophil calcium-dependent functions. Our preliminary data strongly support the ability to detect significant gene expression and eosinophil functional differences in 17q21 polymorphic human immune cells. Greater understanding of how 17q21 variation and associated ORMDL3 expression shape immune function may elucidate why children with risk polymorphisms are predisposed to develop asthma.