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Myocardial biology with a specific focus on the mechanisms underlying cardiac fibrosis and atrial fibrillation


Radcliffe Department of Medicine

About the Project

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.

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).

All our work is facilitated by a number of internal and external collaborations, for example, with the Dept of Pharamoclogy (Oxford), Montreal Heart Institute (Canada), Baylor College of Medicine (USA) and LIRYC Electrophysiology and Heart Modelling Institute (France).

Potential students would have an opportunity to work with a team of enthusiastic, hard working and very friendly scientists on 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 great 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).

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, Trichrome Masson’s staining.
• 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 studies into 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.

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.


Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.


References

Moreira LM, Takawale A, Hulsurkar M, Psarros C, Menassa DA, Antanaviciute A, Lahiri SK, Mehta N, Evans N, Gillis MA, Robinson P, Sparrow AJ, Gillis MA, Ashley N, Naud P, Barallobre-Barreiro J, Theofilatos K, Lee A, Norris M, Clarke MV, Russell PK, Casadei B, Bhattacharya S, Zajac JD, Davey RA, Sirois M, Mead A, Simmons A, Mayr M, Sayeed R, Krasopoulos G, Redwood C, Channon KM, Tardif JC,Wehrens XHT, Nattel S, Reilly S. Calcitonin paracrine signaling controls atrial fibrogenesis and arrhythmia. Nature. 2020. In press.

Reilly S*, Liu X, 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.

Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G, Coudrat T, Danev R, Baumeister W, Miller LJ, Christopoulos A, Kobilka BK, Wootten D, Skiniotis G, Sexton 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 CL, Solaro RJ, Ke Y, Lei M. Editorial: Ca(2+) Signaling and Heart Rhythm. Front Physiol. 2016 Jan 11;6:423. doi: 10.3389/fphys.2015.00423.




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