Grant: Project Grant

Pulmonary arterial hypertension (PAH) is a fatal disease that preferentially targets young women in their 30s and 40s. PAH involves a loss of blood vessels in the lung. This loss leads to increased stress on the right side of the heart and eventual death due to heart failure. Although there is a well-appreciated link between PAH and immune disorders, there is currently little understanding of how changes in the immune system lead to disease in the lung vasculature. Our previous research has shown that particular immune cells, known as Natural Killer (NK) cells, are impaired in PAH patients and animal models of disease. We have also found that genetically modified mice lacking either NK cells or a specific molecule on the surface of NK cells both develop PAH. The current project will use these mouse models, as well as NK cells from PAH patients, to determine exactly how NK cell impairment contributes to disease. This work will focus on identifying the proteins that NK cells use to regulate blood vessel structure in health and disease. Recent studies have also shown that NK cells in humans are diverse. The specific subsets of NK cells that regulate blood vessels will also be identified. Despite the approval of several new treatments, the the annual mortality rate of PAH remains high (~15%), in-line with that of stage 3 breast cancer. This poor survival is linked to the fact that available therapies primarily treat the symptoms of PAH and do not address the underlying factors driving disease progression. Such treatments are also extremely expensive, placing a large burden on the Canadian health care system. The proposed work will help to clarify the role of NK cells in PAH, with the goal of developing new treatments for this devastating disease.