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Using a combination of extensive cell culture and molecular biology techniques, and functional cellular assays to understand molecular mechanisms underlying myocardial structural and electrical remodelling associated with atrial fibrillation.

Reilly

 

About the research

Pursuing a long-standing interest in myocardial pathophysiology, our main focus is to understand molecular mechanisms underlying myocardial structural (e.g., fibrosis) and electrical (changes in ion channels and calcium handling) remodelling associated with atrial fibrillation. The role of microRNA-31 and -34, and calcitonin signalling in myocardial remodelling is of a particular interest in an ongoing work. To investigate these themes we use a combination of extensive cell culture and molecular biology techniques, and functional cellular assays performed in human clinical material and/or in animal models. We actively collaborate with other groups within and outside the University.

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 the Department of Pharamoclogy and Melbourne University).

In parallel, we also search for new mechanisms underlying or causing arrhythmogenesis in atrial fibrillation, 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 and human cardiomyocytes to hormone called calcitonin and its potential role in arrythmogenesis. In parallel, we aim to assess RNA and protein expression profile of calcitonin and calcitonin receptor in patients with sinus rhythm and with atrial fibrillation in clinical samples (serum/plasma and cardiac biopsies). Part of our work aims to understand function of the calcitonin receptor at the molecular level using X-ray crystallography to facilitate more efficient drug discovery pocess (in collaboration with Diamond Light Source, Harwell).

Potential student would have an opportunity to work on one of the outlined above themes with access to a wide range of molecular and cellular biology techniques (see section “Training opporunities”).  The student would learn how to work with human clinical material (serum/plasma samples and cardiac tissue biopsies) and/or animal models (such as mice and guinea pigs). There will be a unique opportunity to work in our collaborators’ labs (Diamond Light Source at Harwell and Dept of Pharmacology at Oxford) and acquire some fundamental techniques in structural biology (i.e., GPCR crystallisation) and cardiomyocytes electrophysiology (i.e., assessment of calcium handling).

Training Opportunities

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

  • Molecular biology, including immunoblotting, immunostaining, ELISA, cloning, RNA/DNA extraction, qPCR, PCR.
  • Assessment of oxidative stress (e.g., measurement of superoxide and nitric oxide production by high performance liquid chromatography, HPLC).
  • Extensive cell culture techniques in primary human and rodent fibroblasts and myocytes, or in cell lines (e.g., HEK293, 3T3 and MCF7).
  • 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).
  • A student will also have an opportunity to get training in animal work with a focus on heart phenotyping relevant to cardiac fibrosis and arrhythomgenesis.
  • Some part of work will involve collection of human serum and cardiac biopsies from patients who will undergo cardiac surgery. A student will be trained in measuring specific biomarkers in these samples as a part of ongoing clinical studies.
  • As a part of ongoing collaboration with Diamond Light Source (Harwell), some training (exclusively related to G protein coupled receptors) will be offered in structural biology (e.g., virus amplification, protein purification and receptor crystallization).
  • Assessment of primary cardiomyocytes’ calcium handling (e.g., contractility, cell relaxation, calcium transients) as a part of internal ongoing collaboration.

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. * - corresponding author; 1 – joint 1st author.
Reilly S, Jayaram R, Nahar K, Antoniades C, Verheule S, Channon KM, Alp NJ, Schotten U, Casadei B. Atrial sources of reactive oxygen species vary with the duration and    substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation. 2011 Sep 6;124(10):1107-17.
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. 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.

 

Supervisors

Other potential supervisors

Assoc Prof Ming Lei
Department of Pharmacology

Dr Isabel Moraes
National Physics Laboratory