Yr Athro Marcela Votruba

Professor Marcela Votruba

Head of School, Optometry and Vision Sciences

School of Optometry and Vision Sciences

Email:
votrubam@cardiff.ac.uk
Telephone:
+44(0)29 2087 0117
Fax:
+44 (0)29 2087 4859
Location:
Room 1.51, Optometry and Vision Sciences, Maindy Road
Media commentator

Mae'r cynnwys hwn ar gael yn Saesneg yn unig.

The work of my laboratory focuses on mitochondrial fusion/ fission genes and neural plasticity in human eye disease. This springs from work on the  pathophysiology of inherited optic neuropathy. We are currently investigating new therapeutic targets for retinal ganglion cell loss, inner retinal degeneration and repair. We are also looking at mitochondrial shaping proteins in retinal degeneration in disease and ageing. We have been interested in the roles of fusion/ fission genes, such as Opa1 and Opa3. Opa1 is known to bind to inner mitochondrial membrane, and when mutated it is believed that the normal balance of mitochondrial fusion and fission is disturbed and programmed cell death is initiated by the loss of mitochondrial membrane potential and the release of cytochrome c. Opa3, like Opa1, is thought to have a role in mitochondrial membrane dynamics, and when mutated in the human, a complex neurodegenerative disease, comprising optic neuropathy secondary to RGC loss, cataract and neuromuscular degeneration, arises.

As part of my role as a Clinician Scientist, I also recruit patients with inherited optic neuropathy for genetic screening and I run a Retinal Clinic and a Genetic Eye Clinic, at the University Hospital of Wales.

Research overview

My goals are aimed at developing a deeper understanding of inherited eye disease and ultimately utilising my position as a clinical ophthalmologist to drive the application of translational research in this area. My primary research interest is the pathophysiology of hereditary retinal and optic nerve diseases. I am currently investigating inherited optic neuropathies, which are a pure model of isolated retinal ganglion cell loss. They demonstrate a central role for mitochondria and show some progressive neurodegeneration. Retinal ganglion cells are the cells that make up the nerve of vision, taking impulses from the retina to the brain. Autosomal dominant optic atrophy is the commonest inherited optic neuropathy. It is caused by mutations in the OPA1 gene, leading to visual loss, which first starts in children and young people. Clinical understanding of the disease is poor, although we have clinical and some pathological evidence that retinal ganglion cells are deficient in the eyes of patients. There is no treatment available. Conventional clinical or research strategies have yet to make any clinical impact on this state of affairs. The mechanism of action of the mutant protein OPA1 is not known, but clues exist suggesting that the shape or function of small organelles in the cell, mitochondria, may be involved. Mitochondria are important in generating energy in the cell. Following on from our work to characterise the disease phenotype and clone the disease gene, my group has analysed the spectrum of mutations in the OPA1 gene and genotype/ phenotype correlations. We have performed functional and expression studies of the OPA1 gene and assessed its wider role in inherited optic neuropathy and we are developing model systems to explore the mechanisms and pathways of RGC loss.

University Education

  • 1981-1984 Undergraduate Pre-Clinical Studies:The Queens College, University of Oxford
  • 1984-1987 Clinical Studies: Green College, University of Oxford Medical School

Academic And Professional Qualifications

  • 1984 BA Hons 2:1 (Oxon)
  • 1987 MA (Oxon)
  • 1987  BM BCh (Oxon)
  • 1989 Primary FRCS
  • 1990 Optics & Refraction, Royal College of Ophthalmologists, London
  • 1991 MRCOphth, London
  • 1992 FRCOphth, London
  • 1999 PhD, University College, London
  • 2000 CCST (December 2000), Royal College of Ophthalmologists, Londonn

Honours and awards

Undergraduate Distinctions

  • 1981 Open Scholarship, The Queens College, Oxford
  • 1984 First Class Hons. Dissertation, Oxford University
  • 1987 Final Year Clinical Prize: Green College, Green College, Oxford

Postgraduate Prizes

  • 1996 The Royal Society of Medicine: Ophthalmology Section- Registrars Meeting: First Prize (Awarded for the Best Paper at Annual Training Meeting)

Research Fellowships

  • 1994 Guide Dogs for the Blind Association Research Fellowship
  • 1998 Wellcome Trust Vision Research Training Fellowship
  • 2002 Frost Research Fellowship
  • 2003 MRC Clinician Scientist Fellowship

Professional memberships

Present Substantive Appointment

  • Aug 2011 Professor and Hon. Consultant in Ophthalmology, Cardiff University and The Cardiff & Vale NHS Trust, University Hospital of Wales.

Previous Substantive Appointments

  • April 2003- October 2003 Full-time Consultant in Medical Retina, Moorfields Eye Hospital, Service Lead for Audit & Clinical Governance, Service Lead for ARMD Research.
  • Oct 2003- Sept 2007 MRC Clinician Scientist Fellow & Hon. Consultant Senior Lecturer, Cardiff University and The University Hospital of Wales.

Speaking engagements

I am STEM Net Ambassador and have been into local schools in Bristol to give talks about science and careers in science and medicine (e.g., Redland High school, Bristol, March 2013).

I am a Mentor for two research fellows.

Invited Lectures

2008

  • OPA1 and inherited neuropathy. ARVO Genetics Workshop, Fort Lauderdale, Florida, USA
  • Mentoring and the Clinician Scientist Experience. Academy of Medical Sciences Meeting, Taunton
  • Genetics of optic nerve disease. Midlands Ophthalmological Society, Leicester
  • Three Blind Mice. British Eye Study Group, Saunton Sands, Devon

2009

  • OPA1 and OPA3 Mice in neurodegeneration. Cardiff Neuroscience Centre, Cardiff University
  • Mouse models of inherited optic neuropathy. Keystone Symposium on Mitochondrial Dynamics and Physiology. Whistler, British Columbia, Canada
  • Genetics of Optic Atrophy. The Royal College of Ophthalmologists Annual Congress, B'ham

2010

  • Nuclear gene OPA1 and OPA3 and mitochondrial function in optic neuropathy. Leeds Institute of Molecular Medicine
  • Mitochondrial shaping proteins in neurodegenerative diseases of the eye. Oxford/ Bristol/ Cardiff Alliance Meeting, Oxford
  • Mitochondrial plasticity and inner retinal degeneration. Vision Research Meeting, Insights into retinal function, repair and angiogenesis, Bristol
  • Opa1- a story of mitochondrial plasticity and inner retinal degeneration. Tennent Institute of Ophthalmology, Glasgow

2011

  • Assessment and diagnosis of optic neuropathies. Clinical Neurology Meeting, University Hospital of Wales
  • Personal experience of mentoring. Academy of Medical Sciences Mentoring Symposium, Cardiff
  • A clinical academic career. Women Professors Forum, Cardiff University

2012

  • Mitochondrial eye disease. UK Eye Genetics Group. University of Bristol
  • Mouse models of mitochondrial optic neuropathy. For: SIG Mitochondrial dysfunction and retinal ganglion cell loss in optic neuropathies: from disease mechanisms to therapeutic strategies. ARVO, May 2012
  • Optic neuropathies. For: European Professors of Ophthalmology, Leuven, June 2012

2013

  • European Neuromuscular Consortium, Naarden, Holland
    Opa1 ocular and CNS effects. Mitochondrial Research Group,  John Radcliffe Hospital, Oxford

Committees and reviewing

I sit of the School of Optometry & Vision Sciences Research Committee (2007- present). Since 2012 I have been Deputy Director of Research and am Chair of the REF Working Group. I am also a member of the Equality & diversity /SWAN ATHENA Committee in OPTOM.

Other Academic Activities

  • Principal Investigator on the MRC Mouse Eyes & Vision Consortium.
  • Editorial Board of Acta Ophthalmologica
  • Editorial Board of the World Journal of Neurology
  • Guest Editor for Drug Discovery Today:   Disease Models (with Prof Ian Jackson, Edinburgh)

External Committees

  • UK Eye Genetics Group Steering Committee
  • Lead Principal Investigator and co-ordinator of the MRC Mouse Eyes & Vision Consortium.

I am Programme Secretary (2011-2016) of European Association for Vision and Eye Research (EVER). I was the Vice President, 2009-2010, and past Section Chair for Molecular Biology/ Genetics/ Epidemiology on the Board of EVER (2004-2009). I was also the Editor of the EVER eNewsletter, which is published four times per year (2005-2009).

Undergraduate Optometry Teaching

I lecture to final year Optometry students on the Abnormal Ocular Conditions Course.

Postgraduate Teaching in Ophthalmology

2009

  • Neuro-ophthalmology case.   Visual recovery in Leber's hereditary Optic Neuropathy. Ophthalmology Postgraduate Teaching, University Hospital Wales, Cardiff

2010

  • Practical genetics of optic atrophy. Ophthalmology Postgraduate Teaching, University Hospital Wales, Cardiff
  • Invited Judge for Vision Research Day, Cardiff.

2011

  • Retinal ganglion cell dendropathy. Ophthalmology Postgraduate Teaching, University Hospital Wales, Cardiff.
  • Invited Judge for Vision Research Day, Cardiff.

2012

  • Mitochondrial eye disease, Ophthalmology Postgraduate Teaching, University Hospital Wales, Cardiff.

Research Interests

My research focus is on the role of mitochondrial dynamics in the pathophysiology of neurodegenerative disease. My focus has been inherited optic neuropathy, with an emphasis on generating model systems to study retinal ganglion cell (RGC) loss and inner retinal degeneration, which occurs as a primary phenomenon in a number of human genetic diseases.

We are studying RGC loss and rescue in vitro and in vivo, and the sequelae of this neurodegeneration on inner retina. To this end, we have been studying retinal ganglion cell lines and primary RGCs, utilising siRNA to explore the effect of opa1 knockdown on cell viability and the mechanism of cell death. We are also exploring the role of neuroprotective agents. OPA1 is known to bind to inner mitochondrial membrane, and when mutated it is believed that the normal balance of mitochondrial fusion and fission is disturbed and programmed cell death is initiated by the loss of mitochondrial membrane potential and the release of cytochrome c. We are also investigating the role of the OPA3 gene in both RGC loss and cataract formation. OPA3, like OPA1, is thought to have a role in mitochondrial membrane dynamics, and when mutated in the human, a complex neurodegenerative disease, comprising optic neuropathy secondary to RGC loss, cataract and neuromuscular degeneration, arises. I continue to recruit patients with inherited optic neuropathy for genetic screening.

Research Alumni

Post- doctoral Research Associates

  • Dr Vanessa Davies
  • Dr Ruby Grewel
  • Dr Andrew Hollins
  • Dr Kate Powell

Professional Training Scheme

  • Rebecca Thirgood

Technical Assistant

  • Elaine Taylor

Summer Students

2005

Marios Sarros. Welcome Trust Summer Scholarship. Mutation screening in inherited optic neuropathy.

2006

Yip WanFen. Welcome Trust Summer Scholarship. Histology of the eye in an opa1 mutant mouse.

2007

Laura Byrne. Welcome Trust Summer Scholarship. Longitudinal phenotyping in ADOA and new aspects of the phenotype- circadian rhythm and cognitive function.

2011

Amanda Mui.   Drp1 visual and neurological phenotyping.

2012

Rebecca Watts. Nuffield Summer Studentship. Mitochondrial Eye Disease.

Grant funding

2003- 2007 MRC Clinician Scientist Fellowship ( £750,000 over 4 years). M Votruba. Sponsor M Boulton.
"The pathophysiology of inherited optic neuropathy".
2005 Wellcome Trust Summer Studentship ( £1800). M Votruba.
"Human mutations in optic atrophy". (Marrios Sarros)
2006-2009     MRC Research Grant   ( £200,005 over 3 years). M Votruba, M Boulton, M Wride.
"OPA3: a novel gene and mechanism in cataractogenesis". Funding RA1A
2006-2008       RoFAR Research Award ( £86,207 over 2 years). M Votruba.
"Erythropoietin neuroprotection in retinal neurodegeneration". Funding RA1A
2006     Wellcome Trust Summer Studentship ( £1360). M Votruba.
Morphological assessment of retina in models of hereditary optic neuropathy. (Yip WanFen).
2007-2009         BBSRC Research Grant ( £255,955 over 2 years). J Morgan, W Drexler, M Votruba, M Wride.
In vitro detection of neuronal programmed cell death by ultrahigh  resolution optical coherence tomography.
2007       Wellcome Trust Summer Studentship ( £1400). M Votruba.
Longitudinal phenotyping in ADOA and new aspects of the phenotype- circadian rhythm and cognitive function. (Laura Byrne).
2008-2011         MRC Research Grant ( £508,864 FEC over 3 years). M Votruba.
"Mitochondrial shaping proteins in models of optic neuropathy ". Funding RA Grade 6 and Technician Grade 4.
2012         Nuffield Foundation Science Bursary for Schools & Colleges: awarded to Rebecca Watts, Supervisor: M Votruba.  Histological assessment of tissue   from Opa1 mutant mouse. £1200
2012-2013 Fight for Sight Dr Hans and Mrs Gertrude Hirsch Grant Award ( £15,000). M Votruba. Find the missing genes: next generation sequencing to accelerate the pace of disease gene discovery in patients with   inherited optic neuropathy.
2013-2014         Thermo Fisher Inspire Award ( £5000). Mechanism of neurodegeneration in mice with mitochondrial dysfunction.
2013-2016     Fight for Sight Research Studentship ( £100,000). M Votruba. Light therapy for optic neuropathy.
2013-2014National eye Research Centre. £60,000. M Votruba. "Idebenone in mitochondrial optic neuropathy".
2013-2015NIHR Rare Disease Translational Research Collaboration ( £200,000). P Yu-Wai-Man, M Votruba, AT Moore.  Mitochondrial optic neuropathies.

Research Collaborators

International

Professor Anne A. Knowlton, M.D., Professor of Medicine and Medical Pharmacology, Molecular & Cellular Cardiology, University of California, Davis, California, USA.

Professor Don Newmeyer, PhD, La Jolla Institute for Allergy and Immunology, La Jolla, CA , USA.

Professor Peter Nuernberg, PhD, Cologne Centre for Genomics, University of Cologne, Germany.

National

Dr Patrick Yu-Wai-Man, MRC Clinician Scientist, Mitochondrial Research Group, The Medical School ¨University of Newcastle upon Tyne,

Professor Patrick Chinnery, PhD FRCP, Wellcome Senior Fellow in Clinical Science, Professor of Neurogenetics and Honorary Consultant, Mitochondrial Research Group, The Medical School¨University of Newcastle upon Tyne

Professor Ron Douglas, Professor of Visual Science: Deputy Head of Department, City University London

Professor Jo Poulton, PhD MRCP, Professor of Mitochondrial Genetics, John Radcliffe Hospital, University of Oxford

Professor Tim Wells, PhD, School of Bioscience, Cardiff University.