Grant: Project Grant

We previously discovered pathologic changes in gene expression that appear to trigger the development of pulmonary arterial hypertension (PAH) and showed that they were mediated by "epigenetic changes" in gene function. Epigenetic means that the changes in DNA function occur without changes in DNA sequence. The changes we identified were caused by increased DNA methylation (addition of methyl groups) of certain genes. We have identified two new gene mutations which may regulate these same DNA methylation epigenetic pathways. If confirmed this would show for the first time that mutations of genes or environmental factors can both result in epigenetic changes that promote development of PAH. Two crucial genes which regulate DNA methylation are DNMT3A and TET2. Mutations which impair their function promote the development of vascular disease, such as coronary disease. We hypothesize that mutations in DNMT3A and TET2 genes contribute to PAH development and represent new therapeutic targets. Our research is uniquely supported by our established access to the genetic material and clinical information from 2500 patients in the PAH Biobank (US) and two large biobanks in the United Kingdom and at Johns Hopkins University, as well as the expertise available at our state of the art translational research facility at Queen's University, the Queen's CardioPulmonary Unit (QCPU). We will expand on promising preliminary data showing DNMT3A and TET2 mutations contribute to PAH, describe the resulting change in gene expression as signatures of PAH and explore the potential to predict disease development and outcome. Finally, we will show that Tet2 & Dnmt3a disruption (whether caused by mutation or by epigenetic down-regulation of gene expression) contributes to PAH development in mouse models where these genes are knocked out. We will test new anti-inflammatory therapies for PAH in these novel mouse models as a step to translating this knowledge into therapy for human PAH patients.