IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY IN MICE

描述（由申请方提供）：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瓣狭窄（SVAS）的血管特征。先前的研究已经表明，患有弹性蛋白介导的疾病的人显示出一系列严重的血管表型;从危及生命的狭窄和高血压到根本没有明显的心血管特征。本申请的目的是鉴定控制这些血管表型的严重性的基因。Eln小鼠提供了一个很好的模型系统，通过它来研究这种变化。本实验室进行的初步研究表明，当Eln小鼠从亲本C57品系异交到不同的近交系背景中时，血管表型发生了变化。对这些动物胎盘的生化分析表明，每种品系沉积的弹性蛋白数量的差异并不影响疾病的严重程度。因此，必须存在弹性蛋白单倍不足表型的其他弹性蛋白非依赖性修饰物，其改变严重血管疾病的风险。对F1代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（C57 x129 Eln）和一种免受与弹性蛋白单倍不足相关的病理学影响的遗传背景（C57 xDBA Eln）。基于这些初步数据，我们建立了以下目标：1）我们将使用F2杂交和SNP基因分型与QTL分析来定位改变弹性蛋白单倍不充分表型表达的遗传位点。2)我们将使用高密度作图技术和RNASeq等位基因特异性分析的组合来缩小影响弹性蛋白介导的血管疾病表达的潜在候选者的位点和数量。血管疾病的弹性蛋白依赖性调节剂的鉴定是重要的，因为它可能代表旨在治疗/预防患有威廉姆斯综合征/SVAS的个体的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.