IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY IN MICE

描述（由申请人提供）：影响弹性蛋白基因的遗传改变导致威廉姆斯综合征和孤立性瓣上主动脉狭窄（SVAS）的血管特征。先前的研究表明，患有弹性蛋白介导的疾病的人在其血管表型的严重程度上表现出一定的范围；从危及生命的血管狭窄和高血压到根本没有明显的心血管特征。这个应用程序的目的是确定控制这些血管表型的严重程度的基因。Eln小鼠为研究这种变异提供了一个很好的模型系统。该实验室进行的初步研究表明，当Eln小鼠从亲本C57菌株异交到不同的近交系背景时，血管表型发生了变化。对这些动物主动脉的生化分析表明，每种菌株沉积的弹性蛋白数量的差异并不是导致疾病严重程度变化的原因。因此，弹性蛋白单倍不全表型的其他弹性蛋白独立修饰因子必须存在，以改变严重血管疾病的风险。对F1动物的分析已经确定了一种具有更严重血管表型的遗传背景（C57x129 Eln）和一种不受弹性蛋白单倍不全病理（C57xDBA Eln）的保护。基于这些初步数据，我们确定了以下目标：1)我们将利用F2杂交和QTL分析的SNP基因分型来定位修饰弹性蛋白单倍性表型表达的遗传位点。2)我们将利用高密度定位技术和RNASeq等位基因特异性分析相结合，缩小影响弹性蛋白介导的血管疾病表达的潜在候选位点和数量。确定血管疾病的弹性蛋白独立调节剂是很重要的，因为它可能代表了治疗/预防威廉斯综合征/SVAS患者心血管疾病的新疗法的潜在靶点。

DESCRIPTION (provided by applicant): Genetic alterations affecting the elastin gene cause the vascular features of Williams syndrome and isolated supravalvular aortic stenosis (SVAS). Previous research has shown that humans with elastin- mediated disease display a range in severity of their vascular phenotypes; from life-threatening stenoses and hypertension to no appreciable cardiovascular features at all. The goal of this application is to identify genes that control the severity of these vascular phenotypes. The Eln mouse provides a good model system through which to study this variation. Preliminary studies performed by this laboratory show alterations in vascular phenotype when the Eln mouse is out-crossed from the parental C57 strain into different inbred backgrounds. Biochemical analyses of the aortas of those animals reveal that differences in the quantity of elastin deposited by each strain are not responsible for variation in disease severity. Consequently, other elastin independent modifiers of the elastin haploinsufficiency phenotype must be present that alter the risk for severe vascular disease. Analysis of F1 animals has identified one genetic background with more severe vascular phenotypes (C57x129 Eln) and one that is protected from pathology associated with elastin haploinsufficiency (C57xDBA Eln). Based on these preliminary data, we established the following aims: 1) We will map genetic loci that modify the phenotypic expression of elastin haplosinsufficiency using F2 crosses and SNP genotyping with QTL analysis. 2) We will narrow the loci and number of potential candidates that affect the expression of elastin mediated vascular disease using a combination of high density mapping techniques and allele specific analysis of RNASeq. Identification of elastin indpendent modifiers of vascular disease is important as it may represent potential targets for new therapies aimed a treating/preventing cardiovascular disease in individuals with Williams's syndrome/SVAS.