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Regulation of colorectal cancer tumour growth by T-type Ca2+ channels and heme oxygenase-1

Project Description

This project will investigate how regulation of T-type Ca2+ channel function by heme oxygenase-1 (HO-1) impacts on the development of colorectal tumour growth. T-type Ca2+ channels are established as important regulators of cancer cell proliferation, providing an important route for Ca2+ entry required for cell cycle progression. HO-1, which generates CO along with biliverdin and Fe2+ via degradation of heme, is inducible in many non-cancerous cell types but is often constitutively expressed in tumour cells. It is closely associated with tumour growth and sensitivity of tumours to radio- and chemotherapy. In pilot studies, we have made the novel observation that CO inhibits T-type Ca2+ channels and so inhibits tumour cell proliferation.

We aim to (i) understand the molecular mechanism of CO regulation of T-type Ca2+ channels (ii) develop inducible colorectal cell lines through which we can control expression of HO-1 and T-type Ca2+ channels to investigate the role of HO-1, CO and T-type Ca2+ channels in proliferation in vitro, and (iii) exploit these cell lines in in vivo xenograft tumour growth studies, inducing protein expression or knockdown via dietary provision of doxycycline. We shall also assess the impact of such protein expression on tumour sensitivity to irradiation.

T-type Ca2+ channel activity and regulation will be monitored directly using patch-clamp electrophysiology. Molecular biological techniques will generate stably transfected colorectal cancer cell lines with which we will inducibly overexpress or knockdown HO-1 and T-type Ca2+ channels. These lines will be used for in vitro assessment of target proteins on proliferation (cell counting and BrdU incorporation, and assessments of viability and apoptosis). We will then progress to injection of these cell lines into nude mice for in vivo xenograft tumour growth studies: growth will be assessed using external callipers and quantitative contrast enhanced high frequency ultrasound which also permits measurement of tumour vascularity and blood flow. We shall also evaluate the vulnerability of tumours to irradiation following doxycycline induction of protein expression / knockdown. The applicants have significant experience and expertise in all required methodologies.

This proposal will determine whether HO-1 inhibits colorectal tumour growth by tonically inhibiting T-type Ca2+ channels. In so doing, we will provide a novel pathway for therapeutic targeting in order to combat colorectal cancer progression. We will also reveal how this signalling pathway impacts on the response to conventional tumour therapy. These studies will validate new targets for future cancer therapy.

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.

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