IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY

弹性蛋白单倍体不足的遗传修饰符的鉴定

• 批准号: 8874263
• 负责人: Beth A Kozel
• 金额: $ 12.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874263
• 关键词: Affect; Alleles; Anatomy; Animal Model; Animals; Aorta; Biochemical; Bioinformatics; Biological Models; Blood Vessels; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Characteristics; Chromosome Mapping; Counseling; Data; Deposition; Development; Disease; Elasticity; Elastin; Future; Gene-Modified; Genes; Genetic; Goals; Human; Hypertension; Inbreeding; Individual; Laboratories; Life; Maps; Mediating; Modification; Mus; Mutation; Pathology; Phenotype; Physiological; Quantitative Trait Loci; RNA Sequences; Research; Risk; SNP genotyping; Severities; Severity of illness; Stenosis; Supravalvular aortic stenosis; Techniques; Variant; Vascular Diseases; Williams Syndrome; aortic arch; base; density; human disease; insight; loss of function; prevent; research study; response; transcriptome sequencing

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.

描述（由申请人提供）：影响弹性蛋白基因的遗传改变会导致威廉姆斯综合征和分离的上主动脉狭窄（SVA）的血管特征。先前的研究表明，患有弹性疾病的人的血管表型严重程度范围。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。该应用的目的是确定控制这些血管表型严重程度的基因。 ELN小鼠提供了一个良好的模型系统，可以通过该系统来研究这种变化。该实验室进行的初步研究表明，当ELN小鼠从亲本C57菌株口气到不同的近交背景时，血管表型的变化。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量的差异不负责疾病严重程度的变化。因此，必须存在其他弹性蛋白单倍不足表型的独立修饰符，以改变严重血管疾病的风险。对F1动物的分析已经鉴定出一种具有更严重的血管表型（C57x129 ELN）的遗传背景，并且一种受到与弹性蛋白单倍氨基弥补相关的病理的保护（C57XDBA ELN）。基于这些初步数据，我们确定了以下目的：1）我们将使用F2杂交和SNP基因分型和QTL分析来修改弹性蛋白单倍舒张液的表型表达。 2）我们将使用高密度映射技术和RNASEQ的等位基因特定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数量。弹性蛋白的血管疾病修饰剂的鉴定很重要，因为它可能代表了针对威廉姆斯综合征/SVA患者治疗/预防心血管疾病的新疗法的潜在靶标。