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  • Svetlana Reilly, Charles Redwood
Reilly

About the research

Cardiac fibrosis is a hallmark histological feature of structural changes in the myocardium associated with virtually all cardiac diseases (e.g., heart failure, hypertension, atrial fibrillation and myocarditis). To date, there is no effective treatment for cardiac fibrosis, as we do not understand the mechanisms contributing or causing it. Our group is very interested in uncovering new potentially important pathways responcible for this condition. Specifically, we investigate the role of G protein coupled receptor (calcitonin receptor) and it’s downstream signalling pathways in fibrogenesis. This work is faciliateted by a number of internal and external collaborations (for example, with Dept of Pharamoclogy, Montreal Heart Institute and Melrbourne University).

Atrial fibrillation is the most common arrhythmia in humans. Changes in calcium handling have been long implicated in this arrhythmia, as calcium is a key ion in electrophysiological function  of cardiomyocytes (a major cell type of the heart); however, the upstream mechanisms underlying changes in calcium handling are still unclear. Thus, we are interested in elucidating electrophysiological response of murine/guinea pig and human cardiomyocytes to a number of pro- and anti-arrhythmic molecules, whose effect on calcium handling and cardiomyocytes function may play a role in arrythmogenesis. Clinical studies in patients are focusing on testing new biomarkers and mediators of the disease (cardiac fibrosis and atrial fibrillation). Part of our work aims to understand function of G protein coupled receptor -calcitonin receptor- at the molecular level using X-ray crystallography in collaboration with Diamond Light Source (Harwell).

Potential student would have an opportunity to work with a team of enthusiastic, hard working and very friendly scientists on one of the outlined above themes with access to a wide range of RNA/molecular and cellular biology techniques (see section “Training opporunities”). There will be a unique opportunity to work in collaborating labs (Diamond Light Source at Harwell, Dept of Pharmacology at Oxford, Institute of Molecular Medicine and Montreal Heart Institute) and acquire some fundamental techniques in structural biology (e.g., X crystallography), cardiomyocyte function (i.e., assessment of calcium handling) and RNA sequencing. The student would also have an opportunity to learn how to work with human serum/plasma samples, heart biopsies and/or animal models (e.g., mice and guinea pigs).

Additional Supervisors:

Prof Ming Lei, PI, group leader, Dept of Pharmacology, University of Oxford

Dr Isabel de Moraes, PI, group leader, Structural Biology, National Physical Laboratories, UK

training opportunities

We offer training in the following techniques relevant to the ongoing projects:

  • Molecular biology, including (but not limited to) immunoblotting, immunostaining, ELISA, cloning, RNA/DNA extraction, qPCR, PCR. 
  • Extensive cell culture techniques in primary human and rodent fibroblasts and myocytes, or in cell lines (e.g., HEK293 and 3T3).
  • Cellular functional studies (including assessment of cell viability, proliferation, migration and wound healing; loss-of- and gain-of-function studies using lipo- or electro-poration transfection protocols with siRNA/vectors).
  • Animal work (mice and guinea pigs) including breeding, colony maintenance, assessment of cardiac fibrosis and arrhythomgenesis in vivo and in vitro.
  • Clinical studies will involve collection of human blood sample and cardiac biopsies for a subsequent measurement of biomarkers in atrial fibrillation and cardiac fibrosis.
  • As a part of ongoing collaboration with Diamond Light Source (Harwell), some training (related to G protein coupled receptors and small peptides) will be offered in structural biology (e.g., virus amplification, protein purification and receptor/peptide crystallization).
  • Assessment of calcium handling (e.g., contractility, cell relaxation, calcium transients) in primary cardiomyocytes as a part of internal ongoing collaboration.
  • Some training in RNA sequencing (including single cell). 

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

publications

Reilly S1*, Liu X1, Carnicer R, Recalde A, Muszkiewicz A, Jayaram R, Carena MC, Wijesurenda R, Stefanini M Surdo NC, Lomas O, Ratnatunga C, Sayeed R, Krasopoulos G, Rajakumar T, Bueno-Orovio A, Verheule S, Fulga TA, Rodriguez B, Schotten U, Casadei B*. Atrial-specific upregulation of miR31 depletes dystrophin and nNOS and leads to electrical remodeling in human atrial fibrillation. Sci Transl Med. 2016 May 25;8(340):340ra74. doi:10.1126/scitranslmed.aac4296; * - corresponding author; 1 – joint 1st author.

Liang YLKhoshouei MRadjainia MZhang YGlukhova ATarrasch JThal DMFurness SGBChristopoulos GCoudrat TDanev RBaumeister WMiller LJChristopoulos AKobilka BKWootten DSkiniotis GSexton PM. Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature. 2017 Jun 1;546(7656):118-123. doi: 10.1038/nature22327. Epub 2017 Apr 24.

Huang CLSolaro RJKe YLei M. Editorial: Ca(2+) Signaling and Heart Rhythm. Front Physiol. 2016 Jan 11;6:423. doi: 10.3389/fphys.2015.00423.