Grant: Doctoral Research Award: Canada Graduate Scholarships

Pulmonary arterial hypertension (PAH) is an incurable disease with a 50% 5-year mortality rate. In PAH, the walls of arteries in the lung become inflamed and thicken, which effectively means less blood can flow through to become oxygenated. The increased resistance to pulmonary blood flow creates back-pressure on the heart, which hinders its ability to pump blood effectively. Our understanding of what triggers the cascade of inflammation in PAH is limited, and because of this, there are no targeted treatments available. My doctoral work will investigate a new theory that dysfunctional immune cells found in the blood that flows through the arteries of the lung secrete factors that mediate inflammation in PAH. As we age, our cells divide and can acquire DNA mutations. In our white blood cells, the accumulation of certain mutations over time can lead to cancers like leukemia. However, since this is a progressive process, there are individuals whose immune cells have started to acquire DNA mutations but who have no overt cancer. That is not to say that these mutations are benign, however. We now know that some genetic mutations render white blood cells dysfunctional by making them secrete more pro-inflammatory molecules than healthy white blood cells. Our lab has found that it is common for PAH patients to have mutations in two key genes. These genes, dnmt3a and tet2, act as a lock and key, respectively, to control which parts of the DNA blueprint are accessible. With a broken lock-and-key system, DNA access, and therefore protein production, can be erratic - in the case of dnmt3a and tet2 mutations, for example, preliminary data suggests that pro-inflammatory proteins are overproduced. For my PhD research, I will characterize exactly how DNMT3A and TET2 mutations in our white blood cells mediate pulmonary hypertension. We may then be able to develop new targeted anti-inflammatory therapies (or re-purpose existing ones) to address the underlying problem in PAH.