Vascular remodelling due to excessive proliferation and apoptosis resistance of
pulmonary arterial smooth muscle (PASMCs) and endothelial cells (ECs) has
been attributed to the pathogenesis of pulmonary arterial hypertension (PAH). It
is an incurable cardiovascular disorder, which leads to right heart failure and
death, if left untreated. Heterozygous germline mutations in the bone
morphogenetic protein receptor type II (BMPR2) have been linked with the
majority (~75%) of the familial form of the disease (HPAH). Mutations in the
BMPR2 gene impinge upon the BMP signalling which perturbs the balance
between BMP and TGF-β pathways leading to the clinical course of the disease.
Current therapies were discovered prior to the knowledge that PAH has
substantial genetic components. Hence, this study aims to identify novel
therapeutic intervention and provide novel insights into how the dysfunctional
BMPRII signalling contributes to the pathogenesis of PAH. This work
demonstrates that cryptolepines and FDA approved drugs (doxorubicin, taxol,
digitoxin and podophyllotoxin) inhibit the excessive proliferation and induce
apoptosis in BMPR2 mutant PASMCs by modulating the BMP and TGF-β
pathways. Moreover, established drug PTC124 has also been tested but has
failed to promote translational readthrough. I have also shown that dysregulated
apoptosis of PASMCs and HPAECs is mediated through the BMPRII-ALK1-BclxL
axis. Finally, the siRNA screen targeting approximately 1000 genes has
identified novel proteins including PPP1CA, IGF-1R, MPP1, MCM5 and SRC
each capable of modulating the BMPRII signalling. Taken together, this study for
the very first time has identified novel compounds with pro-BMP and anti-TGFβ
activities which may provide therapeutic intervention prior to or after the onset of
PAH. / Commonwealth Scholarship Commission in the UK
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/17177 |
| Date | January 2018 |
| Creators | Sharmin, Nahid |
| Contributors | Nasim, Md. Talat, Graham, Anne M |
| Publisher | University of Bradford, School of Pharmacy and Medical Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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