A role for connexin mediated signalling events in the pathogenesis of psoriasis Ref SHLS-143s

Background:
Psoriasis is an inflammatory skin condition, the triggers of which remain unresolved. The skin harbours a microflora of Gram positive bacteria existing in a fine balance between commensal (e.g. Staphylococcus epidermidis) and opportunistic pathogens (e.g. S. aureus). Increased opportunistic bacterial load is associated with psoriatic lesions. Recent evidence suggests this can destabilise skin integrity resulting in disordered cell-to-cell adhesion and proliferation giving rise to ‘flaky’ skin and the induction of innate immune signalling pathways. Connexins (Cx), a family of proteins forming cell-cell communication and adhesion channels are affected by this process. Our recent data indicates that Cx26 mRNA and protein levels are evoked in keratinocytes exposed to peptidoglycan, a key component of the bacterial cell wall and potent inducer of the innate immune response. By contrast Cx43 protein levels are down-regulated. Inhibition of Cx-channel function also reduces induction of pro-inflammatory events. According to recent RNA transcriptome analysis, Cx26 is the 94th most upregulated gene in psoriatic lesions while Cx43 mRNA expression is unaffected. This project will seek to identify the role of Connexins in the progression of psoriasis.

Objectives: Using skin biopsies and cells isolated from normal and psoriatic patients we will determine if specific peptides and/or siRNA targeted to Cx43 and/or Cx26 can restore the balance of connexin-mediated pathways in the skin helping ‘psoriatic’ keratinocytes to re-adhere to each other. We aim to stabilise Cx43 protein interactions associated with cell-to-cell adhesion and to block overactive Cx26 channel behaviour that we propose is associated with pro-inflammatory mediated events. The outputs will provide critical information on the pathology of psoriasis and identify novel molecules with therapeutic potential.

Training will be provided in a diverse range of molecular and cell biology applications, confocal imaging analysis and microbiology with links to use of patient related material and ethical procedures.

The student will join an experienced research team embedded within the Diabetes and Biomedical Science Research Group (http://www.gcu.ac.uk/iahr/researchthemesandareas/long-termconditions/#d.en.57255), Department of Life Sciences, GCU, with benefits from clinical and industrial collaboration. GCU’s position as a world-class research institution has been reaffirmed by the 2014 Research Excellence Framework (REF) results (for details see http://www.gcu.ac.uk/iahr/). The Department has a stimulating multi-disciplinary research environment with an excellent record of publication and research income. Postgraduate students follow a structured developmental plan, within our code of good practice for research. The award winning GCU Graduate School, provides a University-wide strategy for postgraduate research student training in the areas of employability, personal skills, career development, the research environment and the management of research.

The project will be supervised by Dr Patricia Martin (Connexin Cell Biology), Dr Sue Lang (Microbiology) and clinical network support via Dr Mozheh Zamiri and Prof David Burden (consultant Dermatologists, Glasgow).