Genetic control of gene expression during innate immune activation

描述（由申请人提供）：先天免疫反应是由病原体相关分子和toll样受体（tlr）之间的特异性相互作用诱导的，对宿主防御至关重要。最近的研究表明，TLR7和TLRS在病毒感染的先天免疫应答中发挥作用。然而，目前尚不清楚这些先天免疫反应在多大程度上是可遗传的，以及哪些基因位点可能影响这种遗传性。我们的总体假设是，遗传变异存在于对病毒相关分子的先天免疫反应中测量的基因表达水平。我们建议在TLR7（咪喹莫特）或TLR7和TLR8 （R848）特异性合成激动剂的先天免疫应答的背景下研究这一假设。首先，我们将使用经典的双胞胎研究来确定r848诱导的基因表达变化的全基因组遗传力。然后，我们将确定从“HapMap”三联体中分离的b淋巴母细胞样细胞系（B-LCL）中控制tlr7诱导的基因表达遗传变异的数量性状位点（QTL），并将在大量健康个体中对这些QTL中的功能多态性进行精细定位。最后，我们将应用启动子功能和RNA加工的体外分析来了解这些多态性如何影响基因表达。这些研究将确定控制TLR7/8介导的先天免疫反应遗传力的特定遗传位点，以及更广泛地说，环境扰动细胞中基因表达遗传控制的基本机制。这些研究的结果将为常见和新发病毒感染的易感性提供新的潜在标记，并将为发现影响环境刺激反应的功能性遗传变异提供新的实验途径。

DESCRIPTION (provided by applicant): Innate immune responses are induced by specific interactions between pathogen-associated molecules and Toll-like receptors (TLRs), and are critical to host defense. Recent studies have shown a role for TLR7 and TLRS in innate immune responses to viral infection. However, it is unknown to what extent these innate immune responses are heritable and what loci might affect this heritability. Our overall hypothesis is that heritable variation exists in gene expression levels measured during an innate immune response to virus-associated molecules. We propose to study this hypothesis in the context of innate immune responses to synthetic agonists specific for TLR7 (imiquimod) or both TLR7 and TLR8 (R848). First, we will determine genome-wide heritability of R848-induced changes in gene expression using a classical twins study. We will then identify quantitative trait loci (QTL) that control heritable variation in TLR7-induced gene expression in B-lymphoblastoid cell lines (B-LCL) isolated from 'HapMap' trios, and we will fine-map the functional polymorphisms within these QTL in a large cohort of healthy individuals. Finally, we will apply in vitro assays of promoter function and RNA processing to understand how these polymorphisms affect gene expression. The proposed studies will identify specific genetic loci controlling heritability of TLR7/8- mediated innate immune responses and more broadly, basic mechanisms underlying the genetic control of gene expression in environmentally perturbed cells. Results from these studies will provide novel potential markers of susceptibility for both common and emerging viral infection and will characterize a new experimental pathway for discovery of functional genetic variation affecting responses to environmental stimuli.