Dr Patricia Martin

Reader in Molecular Biology

E: Patricia.Martin@gcu.ac.uk
T: +44 (0)141 331 3726
F: +44 (0)141 331 3208

Secretary of the Scottish Skin Biology Club

Profile:

I was awarded my PhD in Molecular Virology at the Department of Biological Sciences, University of Warwick before taking up a Royal Society European Fellowship at the Institute of Virology, Würzburg, Germany. I then spent a further 18 months as a visiting Research Associate in the Department of Entomology, Wageningen Agricultural University, The Netherlands, where I worked on parasitic nematodes. In 1994 I returned to the UK to Cardiff University where I joined MRC supported research teams studying the assembly and function of gap junction intercellular communication channels. In January 2004 I joined the Department of Biological and Biomedical Sciences and am Team Leader of the Connexin Research Group with linking roles in the Diabetes Research Group and a strong interest in molecular mechanisms underlying disease.
Research focus: to develop integrative approaches to study the role of Connexin mediated communication and intercellular signalling in diverse tissue networks. These include:

• Connexins in diabetes (e.g. chronic non-healing diabetic wounds)
• Connexins in epidermal dysplasias
• Connexins in innate immunity.

• Current Roles within the department include:
  • Team leader of the Connexin Research group
  • Diabetes Research Group co-ordinator
  • Programme Leader Biomolecular and Biomedical Sciences ,
  • Department Life Sciences (Bio) Research Seminar co-ordinator, including first and third year PhD days

Research Interests:

Connexins are a family of highly conserved transmembrane proteins that have three main functions:

• they assemble into hexameric ‘hemichannels’ that form a closed half channel in the plasma membrane. Under an increasing range of pathophysiological conditions these channels can be induced to open to release ATP and other molecules with subsequent cellular signalling consequences. A key role for these hemichannels in triggering the innate immune response is emerging.
• two hemichannels from opposing cells dock to form a Gap junction intercellular communication channel that directly connects neighbouring cells in tissues and organs permitting the exchange of small regulatory molecules such as cAMP, IP3 and ATP thus facilitating co-ordinated cellular behaviour.
• Connexins are emerging to have a role in cell adhesion events. Connexin function and expression is dynamically regulated under diverse cellular situations including wound-healing. Connexins are also associated with cell cycle mediated events, tumour suppression and potentially in the control of stem cell differentiation as well as interaction with other membrane associated proteins involved in cell adhesion. Thus Connexin mediated communication events play a key role in maintaining the co-ordination of cellular activities including cell growth and inflammatory mediated responses by regulating the ability of cells to communicate directly with their neighbours and these proteins emerge as prime therapeutic targets for diverse conditions.

Central to wound healing is the rate cells migrate into the wound gap that is impart co-ordinated by a reduction in cell to cell communication via gap junction channels. In chronic non-healing wounds connexin43, is upregulated at the wound edge and differences in channel function in the diabetic state emerge. We have found that small peptides targeting these proteins improve wound closure events in in vitro conditions and may have therapeutic potential.

Mutations in connexins are increasingly associated with genetically inherited disorders eg Cx26, 30 and 31 with hearing defects and skin abnormalities, Cx32 with Charcot-Marie-Tooth X-linked disease, a peripheral neuropathy. Many of these mutant proteins have assembly, trafficking and functionality disorders.

We have developed organotypic epidermal model systems that enable us to probe and dissect the role of individual connexins in epidermal organisation, including wound healing events. The models also offer the potential to assess the therapeutic potential of reagents to overcome the increasing number of connexin-mediated communication-opathies. A number of chimeric connexins linked to reporter proteins such as aequorin and Green Fluorescent Protein (GFP) have further enabled us to study the dynamics of gap junction assembly and functionality in real time under a variety of different physiological situations. The effects of mutant connexins, arising in genetically inherited diseases, on such events is also under investigation.

Key areas of technical expertise: 2D and 3D cell tissue culture, wide range of molecular biology applications including real time PCR and use of PCR arrays; Biochemical based assays e.g. ATP release assays; Cell Biology applications: Western blotting, real time microscopy, immunohisto and immunocytochemistry, Confocal microscopy, calcium imaging and microinjection.
Resource: We hold ethical approval for the GCU Diabetic and non-diabetic skin tissue bank. For further details please contact Dr Catherine Wright.(link to Kates web page).

Selected Recent Publications:

• Easton, J. A., Donnelly, S., Kamps, M. A., Steijlen, P. M., Martin, P. E., Tadini, G., Janssens, R., Happle, R., van Geel, M. and van Steensel, M. A. (2012) Porokeratotic Eccrine Nevus May Be Caused by Somatic Connexin26 Mutations. J Invest Dermatol 17 May 2012; doi:10.1038/jid.2012.143 (IF 6.7)
• Donnelly, S., English, G., de Zwart-Storm, E. A., Lang, S., van Steensel, M. A. and Martin, P. E. (2012) Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis. Exp Dermatol May 2. doi: 10.1111/j.1600-0625.2012.01521.x (IF 4.5)
• Hsu YC, Huan HP, Yu IS, Su KY, Lin SR, Lin WC, Wu HL, Shi GY, Tao MH, Kao CH, Wu YM, Martin PE, Lin SY, Yang PC, Lin SW. (2012). Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells via hepatocyte growth factor signaling. Hepatology. 2012 Apr 13. doi: 10.1002/hep.25773. (IF 10.88)
• Wright, C. S., Pollok, S., Flint, D. J., Brandner, J. M. and Martin, P. E. (2012) The connexin mimetic peptide Gap27 increases human dermal fibroblast migration in hyperglycemic and hyperinsulinemic conditions in vitro. J Cell Physiol 227, 77-87
• de Zwart-Storm, E. A., van Geel, M., Veysey, E., Burge, S., Cooper, S., Steijlen, P. M., Martin, P. E. and van Steensel, M. A. (2011) A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol 164, 197-199
• de Zwart-Storm, E. A., Rosa, R. F., Martin, P. E., Foelster-Holst, R., Frank, J., Bau, A. E., Zen, P. R., Graziadio, C., Paskulin, G. A., Kamps, M. A., van Geel, M. and van Steensel, M. A. (2011) Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes. Exp Dermatol 20, 408-412
• Elbadawy HM, Borthwick F, Wright C, Martin P.E, Graham A. (2011). Cytosolic StAR-related lipid transfer domain 4 (STARD4) protein influences keratinocyte lipid phenotype and differentiation status. Br J Dermatol. 164(3):628-32.
• Robertson J, Lang S, Lambert PA, Martin P.E. (2010). Peptidoglycan derived from Staphylococcus epidermidis induces Connexin43 hemichannel activity with consequences on the innate immune response in endothelial cells. Biochem J. 432: 133-143.
• Johnstone, S. R., Best, A. K., Wright, C. S., Isakson, B. E., Errington, R. J. and Martin, P. E. (2010) Enhanced connexin 43 expression delays intra-mitotic duration and cell cycle traverse independently of gap junction channel function. J Cell Biochem. 110, 772-782
• Pollok, S., Pfeiffer, A., Lobmann, R., Wright, C.W.,Moll, I., Martin, P.E., Brandner, J. (2010) Connexin43 mimetic peptide Gap27 reveals potential differences between the role of Cx43 in wound repair in diabetic and non diabetic cells. Journal of Cellular and Molecular Medicine. J Cell Mol Med 15, 861-73.

Recent Conference presentations (2010-2012):

• P.E. Martin. Differential susceptibility of Connexin26 mutations associated with epidermal dysplasias to peptidoglycan derived from S. aureus and S. epidermidis. Invited Oral Presentation Tenovus 30th Symposium, Glasgow June 2012.
• C Wright, D Flint and P Martin. Cx43, insulin-like growth factor (IGF)-I and IGF-binding protein-5 modulate cell migration in scrape-wounded human keratinocyte and organotypic skin models. British Society for Investigative Dermatology Spring 2012 (CW Invited oral presentation).
• J. Robertson, S.Donnelly, S.Lang and P.E. Martin. Bacterial Cell Wall Components derived from Staphylococcus species have tissue specific effects on hemichannel activity and Connexin expression with consequences on the inflammatory response.Invited Oral Presentation International Gap Junction meeting, August 2011
• S. Donnelly; E. De Zwaart-Storm; M.B. Hodgins, S.Lang, M. Van Steensel, P.E. Martin. Mutations in Cx26 mutations associated with Keratitis-ichthyosis-deafness (KID) syndrome result in aberrant hemichannel activity and an increased inflammatory response. Invited Oral Presentation International Gap Junction meeting, August 2011
• P.E. Martin, C. Wright, S. Webb, M.Watson and S. MacDougall . A discrete point mathematical model for the role of connexins in cell migration events. June 2011, Scottish Skin Biology Club meeting.
• P.E. Martin. Connexins: a novel target for wound healing Maths in Medicine Study Group 2010 see Problem report (http://www.maths-in-medicine.org/uk/2010/diabetic-wounds/).
• S. Donnelly, E.A. De Zwaart-Storm, M.A. Van Steensel and P.E. Martin. Gram Positive Bacterial Cell Wall Components have different effects on Wild Type and Mutant Connexin 26 Hemichannel Activity and subsequent cytokine release in Keratinocytes Poster presentation British Society for Investigative Dermatology Spring 2011.
• P.E Martin. Connexins: a myriad of functions in the epidermis. Invited oral presentation 2nd World Congress in Genodermatology, Maastricht 2010.

Recent Funding:

• The Cunningham Trust (2011-2013): – Dissecting the role of Connexin43-mediated signalling in wound healing: defining Connexin43 therapeutic target domains (£90,000)
• GCU Institute of Health Funding (2010) : Biomathematical modelling of Connexins in wound healing events (2010)(£10,000)
• Zealand Pharma: (2010-2012) Proof of concept studies towards targeting Connexins as therapies for wound healing (£32,000).
• Tenovus Scotland (2010-2012): Defining molecular mechanisms underlying Connexin 26 mediated gap junction disorders of the skin (£10,000)
• British Skin Foundation (2008-2010): Determination of differential gene expression occurring during wound healing (£10,000)
• Chief Science Office (2008-2010): Defining the Molecular Mechanisms Underlying the Role of Connexins in Wound Healing and the Therapeutic Potential of Connexin Mimetic Peptides (£225,000)
• British Skin Foundation (2007-2010): ‘START’ regulation of lipid trafficking during keratinocyte differentiation’ ( 807S £65,000) [co-applicant (PI: Prof Ann Graham, GCU]
• Diabetes UK (2006-2008): The role of myoendothelial gap junction communication in diabetic macrovascular dysfunction (£10,000) [with Prof Ann Graham, GCU].
• BBSRC (BB/C005058/1)(2006-2008) Integrated in vitro model systems for investigating the role of connexins in coordination of cell migration, proliferation and differentiation.( £ 76,000).

Teaching Interests:

Contribute to a wide range of undergraduate and MSc teaching programmes in Molecular and Cell Biology. These include:

• Level 1: The Gene – module tutor
• Level 2: Introductory cell biology – module tutor
• Level 3: Essential Molecular Biology (Deputy Module Leader)
• Level 4: Cell Interactions and Networks (Module Leader)
• Level 4: Offer a range of Honours projects suitable for students with diverse interests in Cell and Molecular Biology, Microbiology and Pharmacology. Projects aim to be tailored to students interests
• Level 5 (MSc): MSc Biomolecular and Biomedical Sciences (Programme Lead) Modules: Biomolecular Studies, Integrated cell Biology (Module leader), MSc project workshop.

Third year undergraduate summer vacation-scholarship scheme: Organise summer vaction-schloraships for interested third year students from sources such as Biochemical Society, Wellcome and Carnegie Trusts. Selected students have the opportunity of 6-8 week summer research projects in GCU laboratories or with supervisor collaborators in Europe.

People:

• The GCU Connexin Research Team
  • Tenured Researcher Fellow - Dr Catherine Wright is now developing linked Research themes

• Post doctoral Research Assistant
  • Rebecca Berends

• PhD Students
  • Steven Donnelly
  • Boatemaa Ofori Frimpong
  • Claire Lorraine
  • Afnan Jan

• GCU Collaborators with overlapping interests in Connexin related disorders and Diabetes
  • Prof Stuart Baird
  • Dr Andrew Collier
  • Dr Sharron Dolan
  • Prof Ann Graham
  • Dr Sue Lang
  • Dr Jane Nally
  • Dr Steven Patterson
  • Dr Catherine Wright
  • Members of the GCU Diabetes Research Group

Collaborations:

• Dr Johanna Brandner: Department of Dermatology, Universitätsklinikum Hamburg-Eppendorf – Germany
• Professor Howard Evans: Department of Medical Biochemistry and Immunology, Cardiff University
• Dr Bjarne Due Larsen: Zealand Pharma, Copenhagen, Denmark
• Dr Brant Isakson: Cardiovascular Research Centre, University of Virginia School of Medicine, Charlottesville, USA
• Professor David Flint, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde
• Professor Maurice van Steensel, Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, The Netherlands
• Dr Steven Webb: Department of Mathematics, University of Strathclyde, Glasgow
• Dr Steven McDougal, Department of Mathematics, Herriot Watt University
• Professor Malcolm Hodgins: Department of Biological and Biomedical Sciences, Glasgow Caledonian University (retired)
• Dr Sheila Graham, Infection and immunity, University of Glasgow

Research Group Alumni:

Previous Postdoctoral Fellows:

• Dr Eve Kandyba (2006-2009) now postdoctoral fellow Center for Regenerative Medicine and stem Cell Research, USC

Previous PhD students:

• Dr Scott Johnstone (2004 – 2007) – AHA postdoctoral Fellow University of Virginia School of Medicine, Charlottesville, USA
• Dr Jennifer Easton (2004-2008) – Postdoctoral research fellow with Prof MA van Steensel, University of Maastricht, the Netherlands
• Dr Jennifer Robertson, (2006-2010) - Postdoctoral Research Fellow GCU

Visiting Researchers:

• Dr Eugene de Zwart Storm( Sept – Dec 2007)

External Links:

• 2011 – present: Secretary Scottish Skin Biology Club
• 2012 – present: British Skin Foundation grants committee

Memberships:

• The Biochemical Society
• British Society of Investigative Dermatology
• European Society for Investigative Dermatology

• The Higher Education Academy

• Knowledge Transfer: Zealand Pharma, Denmark
• Among other things enjoy travelling, hill walking, cycling, horse riding, music and reading
• Member of the GCU-Bio Cycle club

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