Genetics of Pulmonary Hypertension in Mice

描述(由申请人提供)：本申请是对R-21申请罕见疾病研究人员探索性和发展性研究补助金的项目公告的回应(PA-03-171)。PAH是一种以出生后肺动脉压力异常升高和肺血管重构为特征的综合征，最终导致右室衰竭和死亡。在美国，这一发病率为每年百万新发病例。在遗传性和散发性PAH患者中，已发现转化生长因子-β超家族的两个基因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。这种综合征的罕见和治疗效果的混杂严重阻碍了人体研究。因此，动物模型的使用对于加深我们对PAH遗传学的理解是至关重要的。我们最近开发了一种PAH的转基因模型，该模型通过在平滑肌中有条件地表达显性负BMPRII基因来实现。这项建议的目标是使用这个小鼠模型来识别疾病严重程度的修饰基因。为此，我们建议将在PAH小鼠模型中表达的两个转基因转移到另外六个近交系小鼠中。完成后，将使用右室压力的活体测量来对发生PAH的易感性进行排序。然后，一种新的分析方法，基于比较单核苷酸多态(SNPs)存在时的相似性和差异性的算法，将被应用于绘制与生理特征相关的遗传基因座。通过完成这些研究，我们将测试遗传背景是否会影响小鼠PAH的严重程度，并使用新构建的六个转基因菌株，绘制与疾病易感性相关的遗传基因座。

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.