Grant: Master's Award: Canada Graduate Scholarships

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by high blood pressure in the arteries of the lungs. This occurs due to obstructive growth of small pulmonary arteries, which restricts blood flow and places increased demand on the heart, often causing death due to right heart failure. Inflammation plays a major role in this process. Recently, mutations in white blood cells have been found to cause excessive release of inflammatory molecules in cardiovascular disease and blood-related cancers. These mutations are most common in two genes, DNA methyltransferase-3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2), the latter of which our group recently established as a gene in which mutations are associated with PAH. We found that TET2 mutations cause inflammation in PAH patients and that mice without TET2 develop PAH. In addition, exciting preliminary data from our lab suggests that DNMT3A mutations may also cause inflammation and PAH. Therefore, I aim to determine if DNMT3A mutations promote PAH development. Using a mouse model depleted of DNMT3A and exposed to normal or low oxygen conditions (which predisposes to PAH development), I will evaluate the effect of depletion of this gene on PAH development. I will then evaluate the inflammatory pathways involved in PAH development in these mice and investigate anti-inflammatory drugs, such as the interleukin 1? inhibitor Canakinumab, as potential therapeutics. Our results will demonstrate the effects of DNMT3A depletion on the production of inflammation, alterations in blood vessels of the lung, and the development of PAH, and will provide information on the use of DNMT3A expression and pro-inflammatory molecules as potential PAH biomarkers and therapeutic targets.