Investigation of the role of alterations in zinc homeostasis in the pathogenesis and treatment of pulmonary arterial hypertension

Call for Applications for October 2022

Applications are invited for a BHF 4-year MRes/PhD studentship starting in October 2022 at the National Heart and Lung Institute (NHLI) in partnership with the Bioengineering Department at Imperial College. There are four BHF DTP MRes/PhD studentship places (3 studentships funded by the BHF and 1 matched Departmental studentship) and one NHLI Endowment studentship on offer for work specifically within the area of heart failure.

The Cardiovascular Sections of the National Heart and Lung Institute, Imperial College, are located within the Main Campus at South Kensington, the Brompton Campus and Hammersmith/White City Campus. Bioengineering is also located at Main Campus at South Kensington and at White City. Students will have the opportunity to work in state of the art facilities within a highly developed research environment where our ambition is to translate research findings to help those with cardiovascular diseases. All students benefit from a full programme of training in research and transferable skills organised through the Graduate School, the quality of which has been recognised several times at the Times Higher Education (THE) Awards.

Project summary

The BHF 4-year MRes/PhD studentships typically comprises a 1-year MRes in Biomedical Research, followed by a 3-year PhD. During the MRes year, students undertake two laboratory projects which will prepare them for the PhD.

This MRes/PhD study aims to investigate the role of intracellular zinc homeostasis in the pathogenesis and treatment of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is a fatal disease associated with small vessel loss and an obstructive pulmonary vasculopathy that leads to increased pulmonary vascular resistance (PVR), and subsequent right heart failure. There is an unmet need for treatments that can halt/resolve the marked vascular remodelling of resistance vessels that dominates the disease. Zinc homeostasis has received little attention in pulmonary vascular disease (or any other cardiovascular disease). Intracellular labile zinc is tightly regulated. Pioneering work at Imperial (Zhao, et al, Nature, 2015) has shown that expression of the zinc importer, ZIP12, is markedly increased in the remodelled pulmonary vasculature of animal models and patients with pulmonary hypertension and that genetic disruption of ZIP12 expression in the rat attenuates hypoxia-induced pulmonary hypertension. Coupled with laboratory data that ZIP12 regulates cytosolic labile Zn2+ levels and changes in levels is associated with proliferation in pulmonary artery vascular smooth muscle cells in culture, the work highlights a previously unsuspected role for zinc in maintaining pulmonary vascular integrity.

The proposed MRes/PhD study will define how intracellular zinc is regulated in the pulmonary vasculature and right heart cardiomyocytes from rodent models and develop new tools for investigating whether manipulating intracellular zinc is a potential therapeutic option for restoring normal pulmonary vascular structure and function in pulmonary hypertension.

The student undertaking the project will be under supervision of Professors Lan Zhao (Professor of Experimental Medicine), Julia Gorelik (Professor of Cellular Biophysics) and Martin Wilkins (Professor of Clinical Pharmacology), at the NHLI research laboratories located in the Imperial Centre for Translational and Experimental Medicine (ICTEM) Building at Hammersmith campus. Professors Lan Zhao and Martin Wilkins are internationally recognised experts in bench to bedside research of pulmonary hypertension; they employ in vitro, ex vivo and in vivo models and use integrative physiology and pharmacology as well as cutting edge imaging methodology to address important biological questions and develop treatments and biomarkers. Professor Julia Gorelik is a world-authority on high-throughput scanning conductance ion microscopy for studying living cells, e.g. measuring contraction, rhythm and calcium dynamics simultaneously and fluorescence resonance energy transfer (FRET) technique for assessing the compartmentation of signaling molecules, e.g. cAMP and cGMP. The expertise and facilities necessary to ensure the successful completion of this project are available and well established within the NHLI.

Applicant Requirements

Applicants must hold, or expect to obtain, a first or upper second-class honours degree or equivalent in an appropriate subject from a recognised academic institution. Candidates must fulfil College admissions criteria and meet BHF residency requirements.

Applicants should have a BSc or equivalent in biology, physiology, pharmacology, or a related field and interested in developing interdisciplinary research skills in the following specific areas: molecular and cellular biology, in vivo physiology and pharmacology, cardiovascular imaging, therapeutics, and data science.

How to Apply

To apply, please email Jaya Rajamanie ([Email Address Removed]) with the following documents.

• Your CV
• The names and addresses of at least two academic referees.
• A personal statement of no more than 1,000 words explaining your interest in the project and please ensure that you specify your degree classification for your undergraduate and postgraduate degrees.

Selected candidates will get a tour of the relevant campus. Please assume that your application has not been successful if you have not heard from us within a month of the closing date.

Closing date for all applications: 20^th February 2022

Interviews will be held online at the end of March.