Professor Steve Winder

Winder_Steve.jpgProfessor of Molecular Cell Biology
Director of Postgraduate Teaching
Director of External Relations

Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: B2 06 Florey building
Tel: +44 (0) 114 222 2332
Email: s.winder@sheffield.ac.uk

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General

Brief career history

  • 2005-Present: Professor of Molecular Cell Biology, Department of Biomedical Science, University of Sheffield
  • 2003-2005: Reader, Department of Biomedical Science, University of Sheffield
  • 1999-2003: Lecturer (99-01) Reader (02-03), University of Glasgow
  • 1995-1999: Wellcome Trust Fellow, ICMB, University of Edinburgh,
  • 1992-1995: Staff Scientist, Laboratory of Molecular Biology, Cambridge - Advisor, Jake Kendrick-Jones
  • 1988-1992: Postdoctoral Fellow, Biochemistry, University of Calgary, Advisor - Mike Walsh.
  • 1994-1998: PhD, University of Reading, Supervisor - Isabel Forsyth

Research interests

My group is using molecular and cellular approaches to understand the biology of the adhesion receptor dystroglycan. We are focussed on modulating dystroglycan signalling as a therapeutic route to treat Duchenne muscular dystrophy. We are also investigating the functions of dystroglycan in organising and stabilising the nuclear lamina, in cancer and in muscular dystrophies.

Professional activities

  • Member of Editorial Boards of: International Journal of Cell Biology, BioMed Research International, PLoS Currents Muscular Dystrophy, Investigación en Discapacidad, Protein Modules Consortium.
  • External examiner for Molecular Medicine BSc, School of Biological Sciences, University of Edinburgh, Quinquennial review of MSc in Molecular Medicine, School of Biological Sciences, UEA, External Advisory Board for Biomedical Science, International Islamic University Malaysia, External Advisor to the Board of Studies for Biochemistry, Ramnarain Ruia College, Mumbai,
  • Recent Invited Conference presentations: 220th ENMC Workshop on ‘Dystroglycan and the dystroglycanopathies’, Naarden, Holland. EMBO Workshop on ‘The modularity of signalling proteins and networks’, Seefeld, Austria. IIUM Zebrafish Workshop, Kuantan, Malaysia. Action Duchenne International Conference, London. 5th International Workshop for Glycosylation Defects in Muscular Dystrophies, Charlotte, NC, USA.
  • Member of British Society for Cell Biology and Biochemical Society

Full publications

Research

Regulation of dystroglycan function in muscular dystrophy and cancer

The laminin binding protein dystroglycan plays multiple roles in cell adhesion, signalling and membrane cytoskeleton stability. Perturbation of dystroglycan function underlies several muscular dystrophies and is also a secondary consequence of adenocarcinoma progression. Changes to the post-translational modification of dystroglycan are crucial in directing the associations, cellular localisation and ultimately degradation of dystroglycan. Our aim is to elucidate the mechanisms and consequences of these post-translational modifications in order to better understand dystroglycan function and to identify potential therapeutic targets for the treatment of muscular dystrophy or cancer.

We employ in vitro, in/ex vivo fish and mouse genetic models with clinically relevant archival tissue samples or immortalised cell lines. Dystroglycan function is dissected through the use of molecular cell biology approaches, and potential therapeutic targets are assessed in vitro and in vivo. Recently we have developed a novel therapeutic approach for the treatment of Duchenne muscular dystrophy using inhibitors of tyrosine phosphorylation and proteasomal degradation. Through the use of zebrafish screening and phenotypic analysis in mdx mice and human DMD myoblasts we are in the process of validating the potential for repurposed drugs as a precursor to initiating clinical trials. Physiological analysis is carried out I collaboration with Nic Wells at the RVC London.

In vitro models of prostate cancer have revealed a role for the post-translational proteolytic processing and nuclear targeting of dystroglycan. Current efforts are centred around characterising a role as part of the LINC complex in the inner nuclear membrane. These studies form part of an ongoing collaboration with Bulmaro Cisneros, CINVESTAV Mexico City.

SJW_Research

Funding

  • Action Duchenne - Repurposed Cancer Therapeutics as Treatments for DMD
  • Duchenne UK - Are soy products effective in DMD?
  • White Rose - The Dystroglycan LINC
  • Action on Hearing Loss - Dystroglycan function in hearing and hearing loss

Group Members

Ms Tracy Emmerson
Research Associate
Email: t.lariviere@sheffield.ac.uk

Dr Gemma Woodward
Postdoctoral Researcher
Email: g.woodward@sheffield.ac.uk

Mr Matt Cook
PhD Student
Email: mcook4@sheffield.ac.uk

Ms Ruhan A
MSc Student
Email: RA1@sheffield.ac.uk

Lab Extension: 22306

Teaching

Undergraduate and postgraduate taught modules

Level 1:

  • BMS109 Cell Biology
  • BMS110 Research Topics in Biomedicine

Level 4/Maters (MSc)

  • BMS402 Laboratory Research Project (MBiomedSci)
  • BMS6052 Laboratory Research Project (MSc)
Opportunities

Targeting dystroglycan to the nucleus in muscular dystrophy and cancer

This project is eligible for a department scholarship. These scholarships are awarded on a competitive basis – find out more on our funding webpage.

Open to self funded students as well as possible BMS funded.

Background

Dystroglycan is an essential cell adhesion receptor required for early embryonic development. Genetic loss of function gives rise to severe muscular dystrophies with neuronal involvement. Post-translational loss of function also occurs in Duchenne muscular dystrophy and in some cancers. This includes phosphorylation, proteolysis and ubiquitination. Moreover some proteolytic fragments of dystroglycan are targeted to the nucleus where they have effects on transcription. As part of our analysis of dystroglycan post-translational modifications, we identified a lipid modification - palmitoylation of a conserved cysteine residue that could act to anchor bioactive dystroglycan fragments to the membrane, both at the cell surface and in the nucleus.

Aims:

To examine the function of dystroglycan palmitoylation in cellular targeting and in cellular phenotypes associated with muscular dystrophy and cancer.

Techniques:

PCR-based site-directed mutagenesis, and cloning of dystroglycan mutants. Overexpression of dystroglycan mutants in tissue culture cells. Analysis of subcellular distribution of dystroglycan by quantitative immunofluorescence microscopy and cell fractionation. In vitro assays of cell invasion and metastatic growth.

References:

  • Leocadio D, Mitchell A, Winder SJ.
    γ-Secretase Dependent Nuclear Targeting of Dystroglycan.
    J Cell Biochem. 2016 Mar 18. doi: 10.1002/jcb.25537
  • Martínez-Vieyra IA, Vásquez-Limeta A, González-Ramírez R, Morales-Lázaro SL, Mondragón M, Mondragón R, Ortega A, Winder SJ, Cisneros B.
    A role for β-dystroglycan in the organization and structure of the nucleus in myoblasts.
    Biochim Biophys Acta. 2013 1833:698-711
  • G. Mathew, A.Mitchell, J.M.Down, F.C.Hamdy, C.Eaton, D.J.Rosario, S.S.Cross & S.J.Winder (2013)
    Nuclear targeting of dystroglycan promotes the expression of androgen regulated transcription factors in prostate cancer.
    Sci. Rep. 3, 2792.

Informal enquiries about this project welcome.

For further information about these projects and how to apply, please see our PhD Opportunities page.

PhD Opportunities

Selected publications

Journal articles