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Therapeutic resolution of BMPR2-mediated signalling defects in pulmonary arterial hypertension (PAH)


   Faculty of Life Sciences

  , Dr Raj Gopalan, Dr Khaled Assi  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Pulmonary arterial hypertension (PAH) is an incurable and devastating disease and death occurs within 2.5 years of diagnosis. Sustained elevation of the pulmonary arterial pressure (PAP) above 25mm Hg at rest or 30mm Hg during exercise with a normal pulmonary capillary wedge pressure (≤15mm Hg) in the absence of underlying heart, lung or thrombo-occlusive disorders is clinically known as PAH. At present, there is no cure for this disorder.

Current therapies for PAH are very costly with an estimated annual treatment and care expenditure for each PAH patient varying substantially between medications, with £39,000 for iloprost, £23,500 for bosentan, £6,000 for sildenafil and £120,000 for treprostinil with combination therapy potentially reaching an average of a £200-300,000 per year. Therefore, there is an urgent need to develop effective medicines to treat PAH.

We have showed that mutations in a specific gene (called BMPR2) can increase a person's risk of getting PAH and identified factors that regulate the BMPRII-mediated signalling defects in PAH. In this project we will investigate the underlying mechanisms of disease pathogenesis and identify novel therapies for PAH.


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

1. N. Sharmin, C. Nganwuchu and M T Nasim*. Targeting the TGFβ signalling pathway for resolution of pulmonary arterial hypertension. Trends in Pharmacological Sciences: May 2021.
2. G. Durham, J. Williams, M. T. Nasim and T. Palmer. New mechanisms to target JAK-STAT signalling in disease. Trends in Pharmacological Sciences 40: 298-308, 2019.
3. H. M. Chowdhury, N. Sharmin, M. Baran, L. Long, N.W. Morrell, R. C. Trembath and M. T. Nasim*. BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclXL-mediated pathway in pulmonary arterial hypertension (PAH) Human Molecular Genetics, 28:2161-2173, 2019
4. H. M. Chowdhury, M. A. Sidiqui, S. Kanneganti, N. Sharmin and M. T. Nasim*. Aminoglycosides-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that completes with translation termination. Hum Mol Genet. 27: 373-384, 2018.
5. T. Ogo, H.M. Chowdhury, R. Randall, L. Long, J. Yang, R. Schumerly, N.W. Morrell, R.C. Trembath and M.T. Nasim*. Inhibition of the overactive TGFβ signalling by prostacyclin analogues in pulmonary arterial hypertension (PAH). American Journal of Respiratory Cell and Molecular Biology, 48(6):733-41, 2013.
6. M.A Siddiqui, T. Ogo and M.T. Nasim*. Pulmonary Arterial Hypertension: molecular genetic basis and emerging treatments (Invited review). AKMC J 3(2): 30-33, 2012
7. M.T. Nasim*, T. Ogo, H.M. Chowdhury, L. Zhao, C.N. Chen, C. Rhodes, and R.C. Trembath. BMPR-II deficiency elicits anti-apoptotic and pro-proliferative responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Human Mol Genetics (21):2548-58, 2012.
8. M T. Nasim, T. Ogo, M. Ahmed, R. Randall, H.M. Chowdhury, K. Snape, T. Bradshaw, F. Soubrier, I. Jackson, G. Lord, M. Humbert, N. Morrell, R. C. Trembath and R. Machado,. Molecular genetic characterization of Smad signalling molecules in pulmonary arterial hypertension (PAH). Human Mutation 12:1385-89, 2011.
9. M.T. Nasim*, A.G. Ghouri, B.P. Patel, V. James, N. Rudarakanchana, N. Morrell and R.C. Trembath. Stoichiometric imbalance in the receptor complex contributes to the dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet (11):1683-94, 2008.
10. M.T. Nasim* and R.C. Trembath. A dual-light reporter system to determine protein-protein interaction into mammalian cells. Nucleic Acids Res. 33(7): e66 (8 pages), 2005.

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