Genetics of Pulmonary Hypertension in Mice

小鼠肺动脉高压的遗传学

• 批准号: 7005837
• 负责人: KAREN A. FAGAN
• 金额: $ 16.64万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-07 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005837
• 关键词: disease /disorder model; gene expression; gene mutation; genetic susceptibility; genetically modified animals; genetics; laboratory mouse; linkage mapping; model design /development; pulmonary hypertension; quantitative trait loci; single nucleotide polymorphism; transforming growth factors

DESCRIPTION (provided by applicant):This application is in response to a program announcement for R-21 applications for EXPLORATORY AND DEVELOPMENTAL RESEARCH GRANTS FOR INVESTIGATORS IN RARE DISEASES (PA-03-171). PAH is a syndrome characterized by an abnormal increase in pulmonary artery pressure and pulmonary vascular remodeling after birth, ultimately resulting in right ventricular failure and death. The incidence is one new case/million per year in the US. Mutations in two genes in the transforming growth factor-beta superfamily, BMPRII and ALK-1, have been identified in patients with hereditary and sporadic PAH. However, disease phenotype varies widely, and the factors that influence disease severity are poorly understood. Human studies are severely hampered by the rarity of the syndrome and confounding effects of therapy. Thus, the use of animal models is critical to furthering our understanding of the genetics of PAH. We recently developed a transgenic model of PAH by conditionally expressing a dominant-negative BMPRII gene in smooth muscle. The goal of this proposal is to use this mouse model to identify modifier loci for disease severity. To do so we propose transferring the two transgenes expressed in the mouse model of PAH into six additional inbred mouse strains. After that is accomplished, in vivo measurements of right ventricular pressure will be used to rank the strains with respect to susceptibility to developing PAH. Then, a new analytical approach, based on algorithms that compare the similarity and differences in the presence of single nucleotide polymorphisms (SNPs), will be applied to map genetic loci that are associated with the physiological trait. By completion of these studies we will have tested if genetic background influences the severity of PAH in mice and, using the six newly constructed transgenic strains, mapped the genetic loci that associate with disease susceptibility.

说明（由申请人提供）：本申请是针对罕见疾病研究人员探索性和发展性研究补助金 (PA-03-171) 的 R-21 申请计划公告的回应。 PAH是一种以出生后肺动脉压力异常升高和肺血管重塑为特征的综合征，最终导致右心室衰竭和死亡。在美国，发病率为每年百万例新病例。遗传性和散发性 PAH 患者中已发现转化生长因子 β 超家族中的两个基因 BMPRII 和 ALK-1 发生突变。然而，疾病表型差异很大，影响疾病严重程度的因素知之甚少。由于该综合征的罕见性和治疗效果的混杂性，人类研究受到严重阻碍。因此，动物模型的使用对于进一步了解 PAH 的遗传学至关重要。我们最近通过在平滑肌中条件性表达显性失活 BMPRII 基因开发了 PAH 转基因模型。该提案的目标是使用该小鼠模型来识别疾病严重程度的修饰位点。为此，我们建议将 PAH 小鼠模型中表达的两种转基因转移到另外六种近交小鼠品系中。完成后，将使用右心室压力的体内测量来对菌株对发生 PAH 的易感性进行排序。然后，基于比较单核苷酸多态性（SNP）存在的相似性和差异的算法的新分析方法将被应用于绘制与生理特征相关的遗传位点图谱。完成这些研究后，我们将测试遗传背景是否影响小鼠 PAH 的严重程度，并使用六种新构建的转基因菌株绘制与疾病易感性相关的遗传位点。