PROJECT SUMMARY Pulmonary Arterial Hypertension (PAH) is a debilitating and eventually lethal disease that is resistant to current therapeutics. A defining characteristic of PAH is excessive cellular proliferation and remodeling of pulmonary arteries (PA), that results in progressive increases in pulmonary vascular resistance leading to right ventricular failure and death. PAH has a survival time of five to seven years post diagnosis, and most of the current therapies for PAH are vasodilators, which provide symptomatic relief, but do not reverse pulmonary vascular remodeling or stop disease progression. We have discovered a novel gene, PDZ-Binding Kinase (PBK) that is upregulated in hypertensive PA. PBK is a serine/threonine kinase that is overexpressed in a subset of aggressive cancers. The hyperproliferative nature of vascular cells in PAH shares many mechanisms with that of cancer cells, however, the therapeutic utility of targeting PBK in PAH and the mechanisms by which PBK influences pulmonary vascular remodeling are not yet known and are the goals of this proposal. In preliminary experiments in experimental models and human PAH, we show that PBK is robustly upregulated in the medial layer of PA where it overlaps with markers of smooth muscle cells. Gain and loss of function approaches show that PBK expression regulates pulmonary artery smooth muscle cell (PASMC) proliferation. In experimental rat and mouse models of PAH in vivo, we found that selective inhibitors of PBK improve PA remodeling and cardiopulmonary function. To determine the mechanisms underlying increased expression of PBK, we found that the transcriptional co-activator, Yes Associated Protein1 (YAP1) was upregulated in PAH and increased PBK promoter activity and PBK protein expression in PASMC. We employed a proximity ligation approach to identify novel substrates of PBK which revealed Protein Regulator of Cytokinesis 1 (PRC1) as a binding partner. PBK upregulated PRC1 and induced PRC1 phosphorylation and cytokinesis in PASMC. These novel preliminary data inform our central hypothesis that YAP1 upregulates PBK in PASMC to enhance proliferation via PRC1 mediated cytokinesis. Collectively these mechanisms contribute to pathologic pulmonary vascular remodeling and PAH. This hypothesis will be tested using integrated molecular, cellular, genetic, imaging, and translational pharmacological approaches in multiple rodent models including a PBK KO rat. Our long-term goal is to define the key mechanisms by which PBK regulates PASMC proliferation to orchestrate changes in arterial remodeling, a hallmark of PAH. At their conclusion, the proposed studies will move the field forward by defining novel signaling pathways in PAH and a novel mechanism of PASMC proliferation. These studies will also advance the utility of novel therapeutic approaches targeting PBK and cytokinesis to reduce PA remodeling and subsequently improve the morbidity and mortality associated with PAH.
- National Heart, Lung, and Blood Institute: $685,300.00
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