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Adverse myocardial remodelling in cardiac fibrosis and atrial fibrillation


   Radcliffe Department of Medicine

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  Dr S Reilly  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Our main focus is to understand the mechanisms of two major often linked heart conditions cardiac fibrosis and atrial fibrillation.

The main goal of our research is to uncover new important mechanisms underlying and causing these challenging conditions in order to identify new drug-targets. To achieve our research goal we utilise a combination of extensive cell culture, molecular, RNA/DNA/microRNA biology techniques, and functional cellular assays performed in human samples and mice. Some of our projects involve extensive experimental work in clinical human cardiac or blood samples (GMC registration is not needed) and (as a proof-of-principle) animal studies. 

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 accountable for this condition. Specifically, we explore the role of calcitonin receptor, one of G-protein coupled receptors, and it’s downstream signalling pathways in cardiac fibrogenesis [1]. In this project, we also aim to comprehensively study disease-specific transcriptional signature of cardiac fibroblasts using single-cell RNA-sequencing approach [1]. These studies will help us to uncover new important mechanisms causing and contributing to the development of cardiac fibrosis, a very serious incurable condition.

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 muscle cell type of the heart). However, the upstream mechanisms underlying changes in calcium handling in atrial fibrillation are still unclear. Thus, we are interested in elucidating electrophysiological and arrhythmogenic responses of murine, guinea pig and human cardiomyocytes to a number of pro- and anti-arrhythmic molecules like calcitonin [1]. 

In addition, we also investigate how inhibited liver-kinase B1 (LKB1) signalling leads to atrial fibrillation [2]. These studies will help us to identify new players in the arrhythmogenesis of atrial fibrillation.

Clinical studies in patients focus on testing new biomarkers and mediators of cardiac conditions including, but not limited to, cardiac fibrosis, atrial fibrillation and hypertension. 

Animal studies use sophisticated genetically modified mice with target deletion or overexpression targeted to a specific heart chamber (i.e., atria or ventricle) and cell type (i.e., fibroblasts and myocytes) [1]. This part of projects is performed in collaboration with the top international labs (in the USA and Canada).

Structural biology work complements all above studies which aim to understand the function of calcitonin singalling via calcitonin receptor at the molecular level using X-ray crystallography [3]. This work would be performed in collaboration with National Physical Laboratories and Diamond Light Source at Harwell.

All our work is faciliateted by a number of internal and external collaborations including King’s College London, Montreal Heart Institute (Canada), Baylor College of Medicine (USA), Essen Institute of Pharmacology (Germany) and LIRYC Electrophysiology and Heart Modelling Institute (France).

Potential student 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, King’s College London, Montreal Heart Institute and Baylor College of Medicine) and acquire some fundamental techniques in structural biology (e.g., X crystallography), cardiomyocyte function (i.e., assessment of calcium handling), RNA sequencing and designing new animal models. The student would also have an opportunity to learn how to work with human blood 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/electroporation transfection protocols with siRNA/vectors.

·       Animal work (mice and guinea pigs) including breeding, colony maintenance, assessment of cardiac fibrosis and arrhythmogenesis 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) and electrophysiology of cardiomyocytes as a part of internal and international ongoing collaborations.

·       Some training in RNA-sequencing (including single cell).

Additional supervision will be provided by Professor Charles Redwood and Dr Isabel de Moraes.

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.


References

1 Moreira LM, Takawale A, Hulsurkar M, Psarros C, Menassa DA, Antanaviciute A, Lahiri SK, Mehta N, Evans N, 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. doi: 10.1038/s41586-020-2890-8
2 Hulsurkar MM, Lahiri SK, Moreira LM, Ananthasekar S, Nattel S, Reilly S *, Wehrens XHT *. Atrial-Specific LKB1 Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation. Circulation. CIRCULATIONAHA/2020/050190. 2021, in press; *- senior co-authors.
3 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.

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