Project 452132

Pulmonary arterial hypertension (PAH) is a fatal disease that preferentially targets young females. The disease involves a loss of lung blood vessels, leading to increased stress on the right heart and eventual death due to heart failure. Our research has shown that particular immune cells, known as Natural Killer (NK) cells, are impaired in PAH patients and that a protein known as transforming growth factor-b (TGFb) may be driving this impairment. The proposed studies will use genetically modified mice possessing NK cells that are insensitive to the effects of TGFb to determine the precise contribution of TGFb to NK cell-mediated vascular remodeling in the developing lungs of mouse embryos, as well as during the progression of lung vascular diseases like PAH. Single cell RNA sequencing will be used to determine the gene expression profile of NK cells and lung vascular cells in both developing embryos and adult mice exposed to models of PAH, with and without the loss of NK-specific TGFb signaling. This work will provide insights into the molecular processes by which immune cells can contribute to vessel remodeling in the lung and will open up new avenues for drug development based on these processes.