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A novel pathway to exploit in the treatment of pulmonary arterial hypertension: heme oxygenase-1 regulation of T-type Ca2+ channels


Project Description

Pulmonary arterial hypertension (PAH) is a complex disorder which can be familial, or can arise spontaneously, or from induction by drugs / toxins, or as a consequence of other diseases. Importantly, type 2 diabetes is now established as an independent risk factor for PAH. Despite therapeutic developments, prognosis is poor with mortality rates of 15% after 1 year. Despite the complexity of PAH, it is clear that a central feature is an increase in VSMC proliferation, leading to vessel thickening (and sometimes even lumen occlusion), increased vascular resistance and consequent right heart failure. In murine models, knockout of the CO-generating enzyme heme oxygenase-1 (HO-1) dramatically worsens PAH development, and CO inhalation provides protection. Our recent studies have shown that T-type Ca2+ channels can regulate both systemic and pulmonary smooth muscle proliferation, and are inhibited by CO, providing a potential mechanism for the protection against PAH of this gas.

Using a combination of patch-clamp electrophysiology, Ca2+ imaging and other cell biological methods combined with molecular interventions to over-express or inhibit expression of target proteins, this project will explore in depth (i) the involvement of T-type Ca2+ channels in the development of PAH, (ii) how this PAH development can be regulated by HO-1 expression (and consequent production of CO), and (iii) why this might be exacerbated in murine models of type 2 diabetes. The work will also employ novel transgenic mouse models.

As part of this project, the student will also develop skills necessary for the assessment of PAH development in vivo (using lung slices), which will involve new imaging facilities for transgenic mice in Leeds. This will permit full assessment of the role of HO-1 / T-type Ca2+ channels in PAH development in situ.

Thus the student will receive excellent training in a wide variety of complementary, cutting-edge techniques as part of his / her studies, and will join a friendly and dedicated group with a strong track record of excellent publications. The project will also be co-supervised by Dr John Boyle.

Funding Notes

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. Candidate whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:
•British Council IELTS - score of 6.5 overall, with no element less than 6.0
•TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

References

Duckles et al (2015). Pflugers Archiv. 467, 415-427.
Peers, C., (2015) Br. J. Pharmacol. (in press; available on-line).
Elies, J., et al (2014) FASEB J. 28, 5376-5387.
Elies, J., et al. (2014) J. Biol. Chem. 289, 16421-16429.
Boycott, et al (2013) FASEB J. 27, 3395-3407.
Peers, C. (2011) Exp. Physiol. 96, 836-839.

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