Therapeutic resolution of pulmonary arterial hypertension (PAH) by natural products

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder which, if left untreated, leads to heart failure and death. There is currently no cure for this disease. The major aims of the current treatments are to improve symptoms and increase exercise tolerance. We have identified genetic defects in bone morphogenetic protein type II receptor (BMPR2), SMAD1, SMAD4 and SMAD9 genes in patients suffering from this disorder. We have found that these mutations not only reduce BMP signalling, but also activate the transforming growth factor β (TGFβ) signalling pathway. These dysfunctions signalling events lead cells found in the pulmonary arterial wall to multiply too quickly. This means that the pulmonary arterial wall gets thicker, restricting blood flow and increasing blood pressure in the pulmonary artery. We have found that chemicals that either inhibit the TGFβ signaling or promote the BMP signalling reduce abnormal proliferation and show beneficial effects in animal models (rat and mouse) of the disease. Taken together, these observations suggest that compounds that inhibit the overactive TGFβ or promote the BMP pathway may provide a therapeutic effect on people suffering from PAH.

Funding received from the Medical Research Council, Royal Society, Sasakawa Foundation, Commonwealth Scholarship Commission, National Institute of Health Research and a number of venture capital companies enabled us to investigate the consequences of gene defects and screened thousands of compounds including established drugs and natural products. The prospective student will investigate how dysfunctional BMP and TGFβ signalling pathways contribute to disease pathogenesis and identify novel therapeutic intervention using natural products. The project will introduce the student to the broader areas of molecular genetics, biochemistry, drug discovery, pharmacology and translational medicine.

The research activities will be undertaken at the School of Pharmacy and Medical Sciences, University of Bradford. The studies will be performed in the recently renovated laboratories provided with state of the art equipments including high-throughput fluorescence and luminescence plate readers, QPCR machines, gel doc systems and modern tissue culture facilities. The research sits in the context of a highly active research environment at the University of Bradford.