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Contact Person : Professor Paul Riley Vacancy ID : 136257
Contact Phone : 01865 282366 Closing Date : 31-Aug-2018
Contact Email : paul.riley@dpag.ox.ac.uk

Project title

 

The role of hypoxia/HIF-signalling in epicardial cell activation and heart regeneration

 

The role

 

The overall goal is to identify upstream factors which regulate epicardial cell activity and manipulate candidate pathways in a regenerative model organism (neonatal mouse) to determine whether the adult epicardium can be targeted to maintain or enhance cardiovascular regeneration.

 

Background:

Ischaemia and altered oxygen-sensing represents a key environmental cue during myocardial infarction which is principally mediated by hypoxia and HIF1a/2a signalling. The transition from a hypoxic to normoxic environment after birth in mammals has been implicated in accounting for a reduced regenerative capacity following cardiac injury and hypoxia signalling is emerging as a critical factor in the maintenance of proliferative competency of numerous stem cell and progenitor populations. Exposure to normoxia in neonatal mice is thought to promote ROS-mediated P53 DNA damage-repair leading to cell cycle exit and prevention of cardiomyocytes from proliferating; a transition which does not occur in zebrafish. In addition, fate-mapping of hypoxic cells in the mouse heart identified a rare population of cycling cardiomyocytes, with neonatal characteristics including smaller size and mononucleation that contribute to new cardiomyocyte formation in the adult heart.

 

It has not yet been established whether HIFs are required for the formation of the epicardium in the mouse, however, HIF signalling appears to play an important role in the developing avian epicardium. A role for HIF1α in the adult epicardium has recently been inferred via the maintenance of a so-called cardiac hypoxic “niche”.  Several organ-specific stem cell populations reside in specialised niches in the adult, which are characterised by a low O₂ partial pressure (PO₂). Whilst the adult mammalian heart is not hypoxic per se, the ventricular epicardium and proximal sub-epicardium were suggested to act as a hypoxic niche. A population of cells residing in this “niche” were identified as self-renewing, clonogenic and that express cardiac progenitor and epicardial markers. Whilst this study suggests the adult epicardium represents a localised hypoxic environment, the functional role of hypoxia and HIF signalling in adult epicardium itself, either at baseline or following ischaemic injury, remains to be investigated.

 

The transition from hypoxia to normoxia during neonatal stages is coincident with loss of epicardial potential following birth, as first suggested by a study over a decade ago which revealed reduced outgrowth of EPDCs from explants in culture through late development to neonatal (P4) stages in the mouse.  We have revealed that, from the middle of the regenerative period (beyond P4) there is down-regulation of embryonic epicardial genes and a significant reduction in flow sorted Wt1+ (GFP+) cells from the epicardium of Wt1-GFPCre/+ mice; indicative of a state of relative quiescence which persists throughout adulthood.  Furthermore significantly reduced HIF1a immunostaining and hypoxia (Pimonidazole-HCl or hypoxyprobe staining) within the epicardium is evident across P4-P7 stages with an initial peak in HIF1a expression at P4 coincident with the peak in embryonic epicardial gene expression.  We hypothesise, therefore, that transition to a post-natal circulation and normoxia contributes significantly to the quiescence of the epicardium, through to adult stages, coincident with the loss of regenerative capacity.  We now propose to study hypoxia and HIF1a/2a signalling in the context of a potential impact on epicardial cell potential during repair.

 

The specific aims within the programme of research include:

 

  • To determine the spatio-temporal expression of HIF1a and HIF2a and the hypoxic status within the developing, post-natal and adult epicardium.
  • To investigate the effect of MI on epicardial hypoxic status and HIF1/2a expression during neonatal and adult stages.
  • To test the effects of stabilising HIF1a in the context of neonatal heart regeneration.
  • To investigate whether prolonging the hypoxic environment after birth can promote epicardial activation and extend the window of neonatal cardiac regeneration.
  • To determine whether loss of HIF signalling during late gestation may adversely affect regeneration following injury at P1.
  • To investigate whether a hypoxic environment is capable of reactivating the epicardium in the adult mouse post-MI and determine a role for HIF signalling in the default epicardial response to injury.

 

An opportunity is offered for a suitably qualified candidate to work as a postdoctoral research scientist in the group of Professor Paul Riley on a project focused on characterising the role of hypoxia/HIF-signalling in epicardial cell activation and neonatal mouse heart regeneration.  This post will be funded for 3 years on a British Heart Foundation Programme Grant.  The post would be ideally suited to a postdoctoral scientist with experience in working with animal models, preferably surgical experience and ideally competence in establishing myocardial infarction in rodents, tissue and cell culture, and flow cytometry would be an advantage.

 

The post-holder will be based predominantly at the Department of Physiology, Anatomy and Genetics, Sherrington Building, Parks Road, Oxford, OX1 3PT.

 

If you would like any informal discussions about the post, please send a full CV and contact Professor Paul Riley (paul.riley@dpag.ox.ac.uk) otherwise please apply on-line as instructed.

 

Responsibilities

  • Contribute intellectually to:
  • The development of the project and managing his/her own academic research.
  • The management of the project by co-ordinating multiple strands of work to meet deadlines.
  • The discussion of the research findings with other Riley group members and our collaborators Professor Peter Ratcliffe and Dr Tammie Bishop (Nuffield Dept. of Medicine).
  • The presentation of research results for different types of audience.
  • Test hypotheses, analyse data and review/refine working ideas as appropriate.
  • Assist members of the group or people working on collaborative projects to become familiar with new methodologies, act as a source of information and advice on scientific protocols and provide training when needed.
  • Contribute ideas for new research projects.
  • Develop ideas for generating research income, and present detailed research proposals to senior researchers.
  • Prepare scientific reports, represent the research group at external forums (eg scientific conferences) through oral and poster presentations.
  • Write up results for publication in international peer-reviewed journals.
  • Demonstrate initiative and contribute to tasks helpful to the smooth running of the research project.

 

  • Perform any other relevant duties which may be required and which are commensurate with the grade of the post.

 

The post holder will also:

  • Undertake comprehensive and systematic literature reviews and write up the results for publication in peer-reviewed journals.
  • Collaborate in the preparation of scientific reports and journal articles and the presentation of papers and posters at conferences.
  • Supervise project and other students.
  • Represent the research group at external meetings/seminars, either with other members of the group or alone.
  • To ensure that all work in the laboratory is conducted safely, and, in particular, that work is undertaken following the appropriate health and safety policies and procedures for the particular area, without compromise to his/her own safety or that of others who may be affected.

 

Selection criteria

 

Essential – the post-holder will:

  • Hold, or be near completion of, a PhD/DPhil in cardiovascular sciences (or related field) preferably with relevance to development, disease or tissue regeneration)
  • Have expertise in basic molecular biology techniques, preferably including platforms such as Next Generation Sequencing (eg. RNAseq studies); microscopy/imaging, histology and genetic manipulation
  • Demonstrate specialist knowledge related to the project – previous experience in working with the epicardium will be highly valued
  • Have in vitro experience in primary cardiovascular cell cultures and preferably in neonatal and adult mammalian cardiovascular physiology and animal models of cardiovascular disease and/or injury
  • Have a personal licence to work with rodents and zebrafish in the UK or be prepared to obtain such a licence via attendance of in-house courses
  • Have an ability and desire to learn, adapt and optimise existing experimental protocols
  • Have excellent interpersonal skills, a desire to communicate with other researchers with diverse interests and various cultural backgrounds
  • Have willingness to undertake collaborative work with several interacting research groups
  • Be friendly whilst being able to maintain the highest level of professionalism
  • Show enthusiasm for the research proposed and motivation to work effectively, assimilate ideas and to drive work towards publication
  • Be willing to learn relevant cellular, molecular and imaging techniques
  • Have an interest in or preferably experience in using robotics for high throughput screening

 

Desirable –

  • Surgical experience to include generating myocardial infarction in rodents.
  • Previous experience of working with Hypoxia models.
  • Previous publication record & active participation in scholarly meetings.

 

website

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