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Development of a personalized therapy for pulmonary arterial hypertension (PAH)


   Faculty of Life Sciences


About the Project

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.

Like PAH, there are 3000 genetic and acquired disorders caused by nonsense mutations where no therapy is currently available. Attempts have been made to suppress nonsense mutations to restore deficient protein function by small molecule agents but due to lack of selectivity they are not suitable for personalized therapy. Hence, there is an urgent need to develop novel strategies for the resolution of these disorders. Decoding of stop codons to sense codon has been shown in yeast and bacteria, but no RNA-based strategies for mammalian cells have been reported yet. However, we have been successful in developing novel RNA-based therapeutic strategies in promotion of translation readthrough at various nonsense mutations associated with cystic fibrosis, Duchene Muscular dystrophy, Usher syndrome, Hurler syndrome and pulmonary arterial hypertension (PAH) by decoding the stop codon using RNAs.

We have previously developed high-throughput assays, screened thousands of natural products, established drugs, cDNAs, siRNAs and identified novel hits for a number of disorders including pulmonary arterial hypertension (PAH) and myelodysplastic syndrome (MDS). The key goals of this project are to investigate the underlying mechanisms of decoding of nonsense alleles using established assays and determine that novel engineered RNAs can be utilized to develop personalized therapy prior to or following the onset of PAH.

The project will introduce the student to the broader areas of molecular genetics, biochemistry, drug discovery, pharmacology, personalized 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.

Funding Notes

This is a self-funded project; applicants will be expected to pay their own fees or have access to suitable third-party funding, such as the Doctoral Loan from Student Finance. In addition to the university's standard tuition fees, bench fees may also apply to this project.

References

dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet, 2008. 17(11): p. 1683-94.
2. Nasim, M.T., et al., Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat, 2011. 32(12): p. 1385-9.
3. Nasim, M.T., et al., BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH. Hum Mol Genet, 2012. 21(11): p. 2548-58.
4. Chowdhury, H.M., et al., BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension. Hum Mol Genet, 2019. 28(13): p. 2161-2173.
5. Ogo, T., et al., Inhibition of overactive transforming growth factor-beta signaling by prostacyclin analogs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol, 2013. 48(6): p. 733-41.
6. Chowdhury, H.M., et al., Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination. Hum Mol Genet, 2018. 27(2): p. 373-384.
7. Nasim, M.T., et al., HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding. Hum Mol Genet, 2003. 12(11): p. 1337-48.
8. Nasim, M.T., H.M. Chowdhury, and I.C. Eperon, A double reporter assay for detecting changes in the ratio of spliced and unspliced mRNA in mammalian cells. Nucleic Acids Res, 2002. 30(20): p. e109.
9. Nasim, M.T. and I.C. Eperon, A double-reporter splicing assay for determining splicing efficiency in mammalian cells. Nat Protoc, 2006. 1(2): p. 1022-8.
10. Nasim, M.T. and R.C. Trembath, A dual-light reporter system to determine the efficiency of protein-protein interactions in mammalian cells. Nucleic Acids Res, 2005. 33(7): p. e66.

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