Controlling vascular diseases via heme oxygenase-1 modulation of T-type Ca2+ channels.
Vascular smooth muscle cells (VSMCs) control vascular tone and hence blood flow, but also undergo phenotypic changes to become proliferative during adaptation to both physiological and pathological situations. This is a key feature in the development of cardiovascular diseases (e.g. atherosclerosis, systemic and pulmonary hypertension), and limits the success of coronary disease treatments. Collectively, such conditions have a striking impact on global health (>16 million deaths annually worldwide). Thus, controlling VSMC proliferation has tremendous therapeutic potential. The proliferative process is complex, yet two key aspects are of clear fundamental importance both in the systemic and in the pulmonary circulation: (i) altered expression of key VSMC ion channels, and (ii) increased expression of the heme degrading enzyme, heme oxygenase-1 (HO-1). We have shown these two aspects to be intimately linked in a signalling pathway which can be exploited in vascular disease treatment.
There is compelling evidence for the involvement of T-type Ca2+ channels in VSMC proliferation, when their expression increases. Ca2+ influx via T-type Ca2+ channels is necessary for proliferation in vitro and in neointima formation observed following vascular injury. Heme oxygenase (HO) enzymes degrade heme to form biliverdin, Fe2+ and carbon monoxide (CO). HO-1 induction occurs in proliferative systemic vascular diseases e.g. hypertension, atherosclerosis and vascular injury and is anti-proliferative, as well as protecting against inflammation and oxidative stress. CO accounts for many of the effects of HO-1 in VSMCs (e.g. CO inhibits VSMC proliferation following vessel grafting) and is being developed for future cardiovascular therapy.
Based on extensive studies of the regulation of ion channels by CO, our hypothesis is that increased HO-1 expression regulates VSMC proliferation via CO modulation of key ion channels. Focussing on the T-type Ca2+ channel Cav3.1 we will examine the potential for exploiting this regulatory pathway for therapeutic benefit. We have three specific major aims: (i) to define the mechanism(s) of HO-1-derived CO modulation of Cav3.1, (ii) to determine the consequences of such modulation on vascular remodelling using both in vitro and in vivo approaches, and (iii) to examine the potential beneficial effects of modulating the HO-1 / CO / Cav3.1 signalling pathway as a novel approach to treating proliferative vascular diseases.
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.
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.
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