Genetics of Pulmonary Hypertension in Mice

描述（由申请人提供）：本申请是为了响应R-21申请罕见疾病患者探索和医学研究赠款金的计划公告（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，最终导致右心室衰竭和死亡。在美国，发病率为每年1例新发病例/百万例。在遗传性和散发性PAH患者中发现了转化生长因子β超家族中两个基因BMPRII和ALK-1的突变。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。人类研究严重阻碍了罕见的综合征和治疗的混杂效应。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有条件地表达显性负性BMPRII基因开发了PAH转基因模型。本提案的目标是使用这种小鼠模型来鉴定疾病严重程度的修饰基因座。为此，我们建议将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品系中。完成后，将使用右心室压力的体内测量值对菌株对PAH的易感性进行排名。然后，一种新的分析方法，基于算法，比较存在的单核苷酸多态性（SNP）的相似性和差异，将被应用于映射与生理性状相关的遗传基因座。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，并使用六种新构建的转基因品系，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.