Identification of the atrial transcriptional signature of patients who develop atrial fibrillation
Microarray expression analyses have identified differences in the expression of gene sets related to ion channel function and transcription factors in atrial tissue from patients with paroxysmal or persistent atrial fibrillation (AF) versus normal sinus rhythm (SR) and differential expression of miRs involved in the regulation of ion channel subunits have been identified between similar patient groups. However, it is unclear whether these changes are a cause or a consequence of AF.
So far, most of the targets uncovered pertain to AF-induced remodelling (Reilly et al Sci Transl Med 2016), whereas the miR/transcriptional signature of the atrial substrate(s) that promotes incident AF remains to be established. The Statin Therapy In Cardiac Surgery trial (STICS) randomised 1922 patients in SR and no history of AF (67% were statin naïve) to rosuvastatin 20 mg od or placebo (for up to 7 days before elective cardiac surgery and 5 days thereafter). All patients had continuous ECG monitoring for 5 days postoperatively as well as atrial samples collected at the time of surgery (Zheng et al. N. Engl. J. Med. 2016). Using these samples, we have conducted a pilot study comparing patients who developed postoperative AF to matched controls, who remained in SR after surgery. For each sample we obtained gene expression from microarray (Illumina HT-12 v4 BeadChip) and microRNA expression from RNA-Sequencing (Illumina MiSeq platform). Our preliminary data suggest that differences between patients who develop AF after cardiac surgery versus those who remain in SR can be detected, several of which appear to be in transcripts involved in myocardial metabolism and substrate utilisation. We are now planning to expand this study with the aim of identifying candidates to be taken further in the pipeline for subsequent validation and functional assays using techniques (such as qPCR, cloning, reporter assay, gain- and loss-of-function studies, etc) and custom-made genetically modified mouse models.
RNA Biology; cellular electrophysiology; in vivo phenotyping.
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. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
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 support the careers of female students and staff.
||Zheng Z, Jayaram R, Jiang L, Emberson J, Zhao Y, Li Q, Du J, Guarguagli S, Hill M, Chen Z, Collins R, Casadei B. 2016. Perioperative Rosuvastatin in Cardiac Surgery.N. Engl. J. Med., 374 (18), pp. 1744-53. - http://www.ncbi.nlm.nih.gov/pubmed/27144849|
|2||Reilly SN, Liu X, Carnicer R, Recalde A, Muszkiewicz A, Jayaram R, Carena MC, Wijesurendra 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. 2016. Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase.Sci Transl Med, 8 (340), pp. 340ra74. - http://www.ncbi.nlm.nih.gov/pubmed/27225184|
|3||Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K. 2016. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur. Heart J., 37 (38), pp. 2893-2962. - http://www.ncbi.nlm.nih.gov/pubmed/27567408|
|4||Wijesurendra RS, Liu A, Eichhorn C, Ariga R, Levelt E, Clarke WT, Rodgers CT, Karamitsos TD, Bashir Y, Ginks M, Rajappan K, Betts T, Ferreira VM, Neubauer S, Casadei B. 2016. Lone Atrial Fibrillation Is Associated With Impaired Left Ventricular Energetics That Persists Despite Successful Catheter Ablation.Circulation, 134 (15), pp. 1068-1081. - http://www.ncbi.nlm.nih.gov/pubmed/27630135|