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Tanya Shaw

Dr Tanya Shaw

Shaw-Headshot

 

Senior Lecturer in Tissue Repair

 

 

 

 

 

 

 

tanya.shaw@kcl.ac.uk

+44 (0)20 7848 6475

Our research focuses on cell differentiation events in skin wound healing, focussing on normal and pathological scar formation. Scars are an inevitable consequence of trauma and surgery, and thus affect millions of people worldwide. Mild scars may be a minor aesthetic problem, but they can proceed out of control in a subset of the population, resulting in disfiguring, painful keloid scars.

The physical characteristics and appearance of skin are largely attributable to the abundance and arrangement of fibrous extracellular matrix (ECM) proteins (e.g., collagen, fibronectin, elastin) within the dermis. For the most part, dermal ECM is the product of the fibroblast cells comprising the tissue, and scarring occurs when the fibroblasts produce excessive, irregular or disorganised ECM. Damage to the skin triggers activation of normal dermal fibroblasts at the wound margin, which then proliferate, migrate and differentiate to help reconstitute damaged tissue. These cells make an important contribution to wound repair; but unfortunately, they are also a major contributors to scar formation. In the case of keloids, the matrix produced is not only disproportionate, but we have recently discovered using a proteomic strategy that it consists of many unique/abnormal proteins. We propose that this reflects the mis-differentiation of keloid fibroblasts and the epigenetic and signalling mechanisms underlying this change in cell phenotype are currently under investigation. We are using an in vitro  model of ECM production with primary human cells to address these questions, along with the cellular mechanisms responsible for the alignment and organisation of fibrotic matrix.

Epigenetics, the pattern of chemical modifications on DNA and chromatin that influences gene expression (e.g., DNA methylation, histone methylation or acetylation), is now widely accepted to play an integral role in regulating fundamental cellular processes, including differentiation. It is therefore not surprising that we have observed epigenetic changes in wound repair and scar formation. Acetylation (Ac) of specific lysine residues on histones, the addition and removal of which is regulated by histone acetyltransferases (HATs) and HDACs, respectively, is an epigenetic modification that tends to promote gene transcription. This is achieved through Ac-site recognition and binding by bromodomain-containing proteins such as the BET family, which contribute to the recruitment of transcriptional machinery and chromatin remodelling enzymes. We have found an increase in expression of HDAC1/2 in scars compared to normal skin, and are now questioning their functional contribution to the fibrotic process and the potential clinical value of HDAC inhibitors. We are striving to understand the mechanisms by which the HDAC inhibitors affect disease fibroblasts by using discovery proteomics to reveal the non-histone proteins whose acetylation patterns are altered in disease and manipulated by the drugs.

In addition to the ECM-producing characteristics of keloid fibroblasts, also these cells are well-known to have a pro-inflammatory phenotype that perpetuates the chronic inflammation which is a hallmark of disease. We have made significant headway in investigating whether inhibiting BET proteins, a strategy that has been shown to be anti-inflammatory in other contexts, can limit this feature of the keloid cells. Indeed the effects on cytokine production and intracellular signalling look promising, and through this work we have unveiled intriguing disease-specific basal and cytokine-triggered signalling activity. 

Looking forward, we wish to understand how the cell differentiation events leading to normal or pathological scarring are regulated. With respect to paracrine mediators, we hypothesize neuroinflammatory mechanisms are at play. We think this angle has the potential to shed light on the pain and chronic inflammation associated with keloid disease, and could suggest novel therapeutic strategies. With respect to cell intrinsic mechanisms that may inhibit/promote fibroblast mis-differentiation during wound repair, we are exploring the variable developmental history of fibroblasts for clues.

And I often look towards my research past in reproductive biology and ovarian cancer for insight into my current hypotheses and potential future directions. Specifically, I propose that post-ovulatory wound repair provides a remarkable example of tissue repair, and has the potential to reveal intrinsic mechanisms for scar resolution. On the other hand, fibrotic tumour stroma (e.g. in subsets of ovarian cancer patients), as well as the fibrosis associated with other diseases including epidermolysis bullosa, mucous membrane pemphigoid and lichen planus, have the potential to inform us about the common mechanisms of fibrosis.

 

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