Genetics of Pulmonary Hypertension in Mice

University Of Colorado Denver, Aurora CO

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Abstract

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.