Overview
This is an exciting opportunity for a 4-year BBSRC-funded CASE PhD studentship, in conjunction with AstraZeneca, within the world-renowned William Harvey Research Institute at Barts & The London Medical School (SMD) at Queen Mary University of London (QMUL). Applications are invited from highly motivated graduates with a BSc (First or Upper Second) or MSc (Distinction or Merit) in a related biological science. Previous research experience in molecular biology, multiomics, biochemistry and/or pharmacology (including experimental models of disease), would be an advantage. Applicants should have a high level of proficiency in laboratory-based research, data presentation and statistical evaluation, as well as the ability to organise a varied workload and to work within a team. A current Home Office personal licence would also be preferable.
Project background
Enlargement of heart muscle is a common physiological adaptation in pregnancy and following exercise training (Frey et al., 2004; Lovic et al., 2017); therefore, advancing understanding of mechanisms involved in these processes will provide insight into diverse aspects of human health. Cardiac wall thickening is multifactorial and involves complex mechanisms as an adaptive response to cardiac stress that may develop to improve cardiac function (physiological hypertrophy) or heart failure (non-physiological hypertrophy) (Shimizu et al., 2016; Nakamura et al., 2018). Understanding the molecular mechanisms responsible for cardiac cell enlargement is critical to differentiate between beneficial and maladaptive changes permitting identification and detection of targets/patterns in cardiac physiological perturbations. Due to the complexity of these phenomena it is crucial to more fully elucidate the cardiac signalling pathways in the whole heart, in addition to individual cell-types. Recent paradigm shifts enabling study of multiple cell types in concert in a 3D cell culture setting now permit dissection of how cell type susceptibility and intercellular signalling perturbations influence and alter cardiac phenotype, and facilitate translation to in vivo models.
A greater understanding of natriuretic peptide signalling will be critical to differentiate the fate of heart enlargement in cardiac physiology. Atrial (ANP) and brain (BNP) natriuretic peptides are well known to maintain cardiac structure and function through cognate natriuretic peptide receptor (NPR)-A, a guanylyl cyclase-coupled membrane spanning protein (Kuhn et al., 2016). The Hobbs lab has recently reported a key role for C-type natriuretic peptide (CNP) in cardiac physiology (Moyes et al. 2020). In this setting, the biological actions of CNP appear to be mediated via one of two NPRs, guanylyl cyclase-coupled NPR-B and/or Gi-coupled NPR-C, and the balance between these two signalling pathways may determine protective versus detrimental cardiac cell adaptations (Michel et al., 2020). This proposal will investigate such mechanisms more fully in vitro and in vivo, employing unique pharmacological tools & experimental approaches developed by AstraZeneca and novel transgenic mouse lines generated by the Hobbs group.
Project objectives
1. To characterise functional and morphological cardiac perturbations in 2D and/or 3D cardiomyocyte culture systems using novel AZ compounds, with focus on the role of natriuretic peptides.
2. To obtain in vivo translational understanding of functional and morphological cardiac perturbations produced by novel AZ compounds in pre-clinical models of physiological and pathological cardiac pressure overload.
3. To identify and translate understanding of molecular mechanisms/signalling pathways to differentiate between physiological and non-physiological heart enlargement, including proof of concept studies in human heart tissue.
Environment and training
The WHRI is currently the UK’s largest academic pharmacological research institute and has a long history of training talented scientists for careers in cardiovascular sciences and translational research (http://www.whri.qmul.ac.uk/). PhD students join a Translational Cardiovascular Academy and are based in the attractive Charterhouse Square campus in the City of London with access to exceptional scientific and recreational facilities. This training will be an invaluable foundation for individuals wishing to pursue a career in industry or academic research in the area of cardiovascular science.
The student will gain experience and expertise in an array of cell-based molecular and biochemical techniques that will be reinforced by training in experimental (in vivo) models. The latter will comprise more functional pharmacological experimentation, including administration of novel AZ compounds. The student will also gain expertise in data handling and statistical analysis, and attend fortnightly lab/journal club meetings with their supervisors. This will be complemented by a 3-6 month secondment at AstraZeneca (Cambridge, UK) to undertake multiomic analyses/2D & 3D cultures.
Application information:
Interviews are planned for the middle of March 2021. The studentship is to start October 2021.
Your application should include a Curriculum Vitae (CV) and a one-side A4 statement of purpose, setting out your previous academic or other experience relevant to the proposed research; why you wish to undertake this research at QMUL; your previous research or professional training and what further training you think you will need to complete a PhD. In addition, two referees should be named at the end of the statement. At least one reference must be from an academic referee who is in a position to comment on the standard of your academic work and suitability for postgraduate level study. Where appropriate, a second referee can provide comment on your professional experience.
All students must meet English language entry requirements, more information can be found here: https://www.qmul.ac.uk/international-students/englishlanguagerequirements/postgraduateresearch/
Apply here:
https://www.qmul.ac.uk/postgraduate/research/subjects/medicine-william-harvey-research-institute.html
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