Problem Statement: Pulmonary hypertension (PH), a chronic and extremely fatal disease, is characterized by severe increase in blood pressure in pulmonary circulation caused by obstruction in blood flow primarily by uncontrolled growth and proliferation in vessel walls. Despite significant advances in PH drug discovery, a submissive improvement has been seen in therapeutic outcomes and overall patient survival. While one of the main reasons for mediocre therapeutic efficacy of current therapies is the lack of complete understanding of PH pathophysiology and late diagnosis, poor survival benefits of anti-PH therapy can also be attributed to lack of therapies targeting overlapping pathological pathways to subside disease progression.There is an urgent need to develop novel therapies to bridge the gap between current standard of care and the necessity to reverse PH progression. Drug repositioning/repurposing i.e. finding new uses for existing drugs, presents an attractive approach to explore the utility of therapeutic molecules currently approved for a different indication, in targeting pharmacological pathways associated with PH progression. Hypothesis: Overall hypothesis of this grant proposal is that screening of currently FDA approved drug molecules for anti-PH efficacy will result in discovery of a potent drug molecule with multifaceted mechanism of action, capable of not only providing symptomatic relief but also reversing PH progression. Approach: In this application, a commercially available library of over 2,300 drug molecules will be screened against PH pathogenicity. The drug library will be screened in-vitro to identify molecules with efficacy in curbing hyper-proliferation of pulmonary vascular cells. Identified molecules will be counter-screened for cytotoxicity and efficacy in modulating molecular markers of PH progression. Top 3 validated hits will be tested in-vivo in SU5416/Hypoxia induced PH rat model to determine efficacy in ameliorating disease symptoms and reversing disease progression. Impact: Success of this proposal will have a profound impact on PH drug discovery landscape. Current therapies do not provide a viable treatment option due to expensive costs and moderate disease reversal, not to mention severe adverse effects associated. Repositioning of an existing off-patent drug for PH treatment will provide an avenue for developing a novel and affordable PH therapy with superior therapeutic outcomes.
|Program type||AHA Institutional Research Enhancement Award (AIRE|
|Effective start/end date||04/01/2018 → 06/30/2020|