There is a fundamental gap between our current treatment for Pulmonary Arterial Hypertension (PAH) with primarily vasodilators, and the need to reverse the occlusive vasculopathy of pulmonary arteries that results in increased pulmonary vascular resistance and right heart failure. Increasingly, Bone Morphogenetic Protein Receptor 2 (BMPR2) signaling is recognized as a key pathway and potential master switch in PAH with reduced BMPR2 expression implicated in vascular cell proliferation and occlusive vasculopathy. The overall goal of this proposal thus is to develop new therapies to reverse the occlusive vasculopathy by novel pathways that increase BMPR2 expression. The mechanism by which BMPR2 is downregulated in PAH patients is not known. Strategies to increase BMPR2 signaling have shown promise in experimental pulmonary hypertension yet most approaches still face many obstacles before they can be used clinically. Thus, identifying BMPR2 modifier genes that could be harnessed with repurposed drugs to increase BMPR2 expression would be a promising strategy to improve PAH with a clear path to therapeutic translation. Our proposal has three significant parts, which are represented by our three specific aims: First, we will focus on novel BMPR2 modifier genes, Fragile Histidine Triad (FHIT) and Lymphocyte specific protein tyrosine Kinase (LCK) that we identified in an siRNA High Throughput Screen (HTS) and that are not only functionally important in PAH but also highly represented in a meta-analysis of PAH transcriptomic databases. Our strong preliminary data showed that decreased expression of FHIT and LCK resulted in reduced BMPR2 mRNA expression and impaired function of pulmonary vascular cells. Our studies on human PAH lung tissue, endothelial as well as immune cells suggested that FHIT and LCK are downregulated in PAH and modify disease penetrance in familial PAH. Second, we will determine how FHIT and LCK regulate BMPR2 on the epigenetic and transcriptional level using candidate and unbiased profiling assay approaches. Third, we will determine whether a drug that increases FHIT, Enzastaurin, reverses the abnormal phenotype of human vascular cells and experimental pulmonary hypertension, thus offering a clear path to a therapeutic translation. Three innovative aspects underlie our approach: (1) conceptually, we will target BMPR2 expression by modulating two novel genes that have not been describe in PAH before (2) technically, we used a novel siRNA high Throughput Screen that has not been used to identify BMPR2 modifier genes in PAH and (3) pharmacologically, we will repurpose existing drugs which not only saves time and expense but can speed their adoption in the clinic because of known safety and toxicity information from regulatory agencies. The contribution of our proposed research is highly significant to the field o PAH, as it utilizes novel pathways to regulate BMPR2 gene expression by repurposing drugs not previously linked to either the receptor or to PAH.
Our studies will define new therapies to reverse the occlusive vasculopathy in pulmonary arterial hypertension by targeting novel pathways that increase expression of Bone Morphogenetic Protein Receptor 2 with repurposed drugs. Thus, the proposed research is relevant to the part of the NHLBI's mission that pertains to stimulating basic discoveries that have great potential to be translated into clinical practice.
|Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23|