Pulmonary arterial hypertension (PAH) is a severe and life-threatening disease that is characterized by elevated pulmonary blood pressure. A challenge in treating PAH is that while the current generation of therapeutics alleviate symptoms, they fail to target the underlying causes of the disease. Initially it was thought that PAH is caused by increased pulmonary vasoconstriction; it is now understood that PAH mainly results from remodeling of the pulmonary vasculature. Further characterization of the underlying mechanisms of PAH will identify newpharmacological targets to treat PAH. In this dissertation I seek to address this challenge from three distinct perspectives. In Chapter 2, I investigated the signaling network downstream of TGFβ and highlighted the MRTF/SRF pathway as potential therapeutical targets for PAH given its pivotal role regulating expression of contractile proteins in PASMCs. In Chapter 3, I aim to test whether TGFβ and the silencing of BMPR2, a member of the TGFβ family of receptors, contribute to the activation of lung fibroblasts in vitro. My results presented do not replicate the role of BMPR2 silencing found in other studies. This could be caused by the relatively short duration of BMPR2 silencing in our system. Finally, in Chapter 4, I perform a combined meta-analysis of several publicly available transcriptomic datasets of lung tissues from PAH patients. Using this approach, I identify PAH-associated signaling pathways, and chemical compounds which reverse a PAH-associated gene expression signature. My findings also suggest that while we bin PAH patients into various subtypes in the clinic, on a transcriptional level, PAH patients tend to group into distinct gene expression clusters without relying on their clinical subtype. These findings improve our understanding of PAH biology and also highlight several potential drug targets for PAH.
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