Genetic and Environmental Pathogenesis of Primary Pulmonary Hypertension

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is a progressive, fatal disease, which threatens the lives of thousands of patients across all age groups. In a recent important advance, mutations in bone morphogenetic protein receptor 2 (BMPR2) have been associated with both familial and sporadic PPH. Our hypothesis is that other genes and biologic events participate in the development of familial PPH, because only 20% of persons with a BMPR2 mutation ever develop PPH. Our target goals are to identify the modifying genes and environmental features that regulate the clinical expression of mutations in BMPR2; to develop understanding about how BMPR2 mutations result in disease; and to identify the undiscovered mutations which cause PPH. The program forms a structural basis to enhance existing collaborations among experienced investigators from six disciplines to optimize progress in the study of PPH. The program will utilize the unique resources of our database and specimen bank developed from 116 PPH families across the US. In families with mutations not yet identified, we will search for alterations in the BMPR2 gene, including promoter and intronic regions, and search for chance recombination events which could confirm another locus near 2q33. Experimental approaches for identifying modifier genes will include genome wide single nucleotide polymorphism and microsatellite scans in large families with known mutations, examination of mitochondrial DNA haplotypes and candidate genes as modifiers, including NOS-1, NOS-3, and the serotonin transporter. We will study the perceived risks and benefits of genetic testing and counseling in many individuals in families at high risk for PPH. We will also identify genetic modifiers of BMPR2 in mouse models of pulmonary hypertension. We will determine the functional mechanisms by which variations found in the BMPR2 alleles alter BMP signal transduction by defining the biochemical effects of the mutant proteins on signaling pathways. The proposal emphasizes that the common themes, complementary expertise and unique technologies assembled into a coordinated program will be more creative, more productive and more likely to advance understanding of the molecular pathogenesis of PPH.