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F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S

B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M M E

P R O J E C T S Y N O P S I S T E M P L A T E 1

Project title Identification of specific cardiac proteins dysregulated in PKP2-associated

arrhythmogenic right ventricular cardiomyopathy patients

Mentor 1 Henning Bundgaard, MD, DMSc , Professor of Cardiology, The Heart

Centre, Rigshospitalet (henning.bundgaard@regionh.dk).

Mentor 2 Alicia Lundby, PhD, Associate Professor, Department of Biomedical Sciences and

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and

Medical Sciences, University of Copenhagen (alicia.lundby@sund.ku.dk).

Framework The candidate will focus on the heart disease arrhythmogenic right ventricular

cardiomyopathy (ARVC). On the hospital side, he/she will work in the clinic with

cardiologists, managing these patients. This offers a first-hand knowledge of

challenges faced by the patients. In our unprecedented “precision diagnostics

program” we have quite unusually gotten approval for harvesting cardiac biopsies

from ARVC patients. The candidate will work with the basic science team - experts

in cardiac proteomics and use state-of-the-art mass spectrometry technologies to

quantify the protein expression in biopsies. The clinical and basic science teams

work closely together to ensure the best possible and most promising experimental

design to answer the clinical challenges and to optimize inclusion of patients. It is

anticipated that we will identify novel specific molecular pathways that are

dysregulated in ARVC patients. The knowledge obtained will be taken back to the

patients and used clinically.

Project

synopsis

1 The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the

admissions process to the programme.

PAGE 2 OF 2 ARVC is an inherited cardiac disorder presenting in the young with malignant

arrhythmias, risk of sudden death and heart failure. Current therapy consists of

extreme exercise restriction, defibrillator implantation, ablation and in some cases

heart transplantation. The majority of known ARVC variants reside in the gene

PKP2. PKP2 is located in an inter-cardiomyocyte adhesion complex. Emerging

evidence suggests PKP2 is involved in translating information from the site of cell-

cell contact into intracellular signals. We propose the applicant to combine results

of deep phenotyping and results of state-of-the-art mass spectrometry technologies

of studies of cardiac biopsy material from 1) ARVC patients and 2) a murine model

of ARVC - to uncover 1) proteins dysregulated in ARVC and 2) intracellular signaling

pathways dysregulated upon exercise in a PKP2-dependent manner. The findings

will allow the candidate to elucidate novel roles for PKP2 of utmost importance for

ARVC pathogenesis.

Profile of

potential

fellow

The candidate should either have experience in cardiac biology or in

proteomics/bioinformatics:

Either

-experience with high-resolution proteomics (LC-MS/MS, Orbitrap)

-bioinformatics

Or

-molecular cardiac studies (preferentially focused on cardiomyocytes)

-desmosome biology

-phosphorylation mediated signaling pathways

-cardiac physiology

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M E N T O R C V T E M P L A T E 1

Name Henning Bundgaard

Title Ph.D., Dr.Med.

Current

department(s)

Heart Center, Rigshospitalet

Department of Clinical Medicine, University of Copenhagen

Current position(s) Professor, consultant in cardiology

Education/training 2005: Dr.Med. Faculty of Medicine, University of Copenhagen

2002-2004: Fellowship in cardiology / research in Sydney, Australia

1997: Ph.D. Faculty of Medicine, University of Copenhagen 1988: MD, Faculty of Medicine, University of Aarhus

Scientific career

profile

Research experience: Consultant in cardiology since 2007 and Professor since

2015. Head of The Capital Regions Unit for Inherited Cardiac-vascular Diseases

since 2007. Head of the Clinical Academic Group; Precision diagnostics in

cardiology, 2017. Areas of expertise: Cardiology, inherited cardiac disease. Ph.D.

and doctoral thesis in Na,K-ATPase research in animal and human models using a

wide range of technologies including patch-clamping. This formed the basis for my

interest in cellular mechanisms and paved my way into cardio-genetics.

Research group and scientific environment: The Clinical Academic Group I am

heading has the purpose to develop “precision diagnostics in cardiology” using

omics combined with deep phenotyping. This represents a large research

consortium with 5 cardiac departments and 6 departments at University of

Copenhagen. The concept is to bridge clinical research and basic research

competencies.

Joint publications and/or active collaborations; Researchers from Sidney, Boston,

Prague, Oslo, Lund, Reykjavik, Oxford, Amsterdam and London. All collaborations

related to genetics/cardiology or Na,K-pump regulations.

PI / Co-PI of former and present large Danish nationwide clinical studies.

Bibliometric

summary

Author or co-author of more than 170 articles (First author: 23, corresponding

author: 26). Scopus H-index 28. ORCID id: 0000-0002-0563-7049.

Selected publications:

1. Broendberg AK, Nielsen JC, Bjerre J et al. Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. Heart. 2017;103(12):901-909

2. Nouhravesh N, Ahlberg G, Ghouse J et al. Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy. Mol Genet Genomic Med. 2016 ;4(6):617-623

3. Bundgaard H, Axelsson A, Hartvig Thomsen J et al. The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur J Heart Fail. 2017;19(4):566-575

4. Veselka J, Jensen MK, Liebregts M et al. Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry. Eur Heart J. 2016;37(19):1517-23

5. Behrens I, Basit S, Lykke JA, et al. Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy. JAMA. 2016 8;315(10):1026-33

6. Axelsson A, Iversen K, Vejlstrup N et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015;3(2):123-31

7. Fanoe S, Kristensen D, Fink-Jensen A et al. Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management. Eur Heart J. 2014 1;35(20):1306-15

8. Thorsen K, Dam VS, Kjaer-Sorensen K et al. Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nature Communication. 2017.

9. Iversen K, Ihlemann N, Gill SU et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med. 2018 Aug 28. doi: 10.1056/NEJMoa1808312. [Epub ahead of print] PubMed PMID: 30152252.

10. Bundgaard H et al. A Novel Familial Cardiac Syndrome. NEJM, in press.

Contributions to

mentoring,

training,

supervision

My philosophy is to mentor the young researcher to become independent by

involving him/her in all research aspects; propose on novel ideas, develop study

designs, write funding applications, participate in and head meetings, write

summaries, establish contacts to other groups, guide younger colleagues –

everything with focus on trust and responsibility. I always make myself available on

very short notice to discuss, support and make decisions if needed.

Past supervisor for 8 Ph.D. projects. Current supervisor for 6 Ph.D. students and 6

medical students. All my former Ph.D. students have obtained or are close to

obtain the career path they were originally aiming for. Two of these in the private

sector.

I am/have been teacher of pre- and post-graduates in medicine and other health professions for the past 15 years.

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M E N T O R C V T E M P L A T E 1

Name Alicia Lundby

Title PhD

Current

department(s)

Department of Biomedical Sciences and Novo Nordisk Foundation Center for

Protein Research, Faculty of Health and Medical Sciences, University of

Copenhagen.

Current position(s) Associate Professor

Education/training Education:

Ph.D. in Health and Medical Sciences (2009).

M.Sc. in Physics (2005).

Training:

Post Doctoral Research Fellow in Quantitative Proteomics. Novo Nordisk

Foundation Center for Protein Research. Advisor: Prof. Jesper V. Olsen (2009-

2011, 2012-2014)

Post Doctoral Research Fellow in Human Population Genetics, The Broad Institute

of MIT and Harvard, Cambridge, USA. Advisor: Prof. Mark Daly (2011-2012)

Visiting scientist in genetically encodable voltage sensors, RIKEN Brain Science

Institute, Saitama, Japan. Advisor: Prof. Thomas Knöpfel (2007-2008)

Visting research student, ion channel research. Department of Biology, University

of California at San Diego, USA. Advisor: Prof. Mauricio Montal (2003-2005)

1 Do not exceed two pages.

The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the

admissions process to the programme

PAGE 2 OF 3 Scientific career

profile

Research field: Molecular regulatory mechanisms of the heart.

Ultimate goal: To identify novel protein targets for intervention of cardiac

diseases.

Key competencies: Applying unbiased large-scale experimental approaches

combining state-of-the-art proteomics and genetics technologies to explore the

cardiac protein landscape to identify novel proteins of key importance for human

cardiac physiology.

Main collaborators: Professor Mario Delmar, New York University. Professor

David Milan, Harvard Medical School. Professor Mark Boyett, University of

Manchester.

Bibliometric

summary

Articles: 25, First authorships: 15, Corresponding authorships: 4, h-index: 17

10 most relevant articles

1: D’Souza A et al. Circulation Research. 2017 Aug 17. doi:

10.1161/CIRCRESAHA.117.311607.

2: Van der Harst P et al. J Am Coll Cardiol. 2016 Sep 27;68(13):1435-48. doi:

10.1016/j.jacc.2016.07.729.

3: Lundby A et al. Nature Methods. 2014 Aug;11(8):868-74. doi:

10.1038/nmeth.2997. Epub 2014 Jun 22.

4: Arking DE et al. Nature Genetics. 2014 Aug;46(8):826-36. doi:

10.1038/ng.3014. Epub 2014 Jun 22.

5: Lundby A et al. Cell Cycle. 2013 Aug 06; 12(17)

6: Lundby A et al. Science Signaling. 2013 Jun 4; 6(278) rs11

[DOI:10.1126/scisignal.2003506]

7: Lundby A et al. Cell Reports. 2012 Aug 30;2(2):419-31. doi:

10.1016/j.celrep.2012.07.006.

8: Lundby A et al. Nature Communications. 2012 Jun 6;3:876. doi:

10.1038/ncomms1871.

9: Lundby A et al, Heart Rhythm, 2010 May; 7(5):708-713

10: Lundby A et al, Heart Rhythm 2007 Dec; 4(12):1532-41.

Contributions to

mentoring,

training,

Our research group has an overall research theme, but independent research

projects are developed together with the student, such that the focus of the

PAGE 3 OF 3 supervision project is within the strengths of the student.

Our group was formed three years ago, and hence only three students have left.

These three currently hold positions at a Max Planck Institute, Agilent and Novo

Nordisk. In the group we currently have 2 senior post doctoral fellows, 2 Ph.D.

students and one M.Sc. student. A hiring process for recruiting two additional

post docs is ongoing.

Contribution to teaching on graduate level:

- Co-organizer of graduate course on ion channel regulation (May 2018)

-Organizer of National PhD network seminar at The Royal Danish Academy of

Sciences and Letters (May 2015).

-Co-organizer of National PhD network seminar at The Royal Danish Academy of

Sciences and Letters (May 2013).