A University of Queensland research team is unravelling the mysteries of keratins, the major structural proteins of the skin, which are hot medical property in the United States and Europe because of their potential role in wound healing and gene therapy.
The Skin Research Laboratory in the University's Biochemistry Department, led by Dr Joe Rothnagel, is painstakingly mapping the biology of keratins and their role in protecting skin cells from damage.
Recent studies have discovered that some types of keratins are rapidly induced whenever the skin is traumatised by wounds, sunburn, skin tumours or diseases such as psoriasis.
However, it is not known whether expression of these proteins at damage sites plays a significant role in healing.
Although scientists have patented keratin genes anticipating their role in gene therapy, they have yet to determine the significance of expression of different keratin gene pairs in wounded and healthy skin, and differential expression at different body sites.
The University of Queensland laboratory, funded by a $500,000 National Health and Medical Research Council grant, aims to work out the biology of keratins, including their expression in both normal and diseased skin.
The long-term project also has researchers examining the role of mutations in keratin genes in certain genetic skin disorders.
Approaches include gene cloning and analysis, and the use of transgenic mice to examine the effects of mutant keratins and to determine their relationship to known genetic diseases.
Dr Rothnagel said keratins were found in a number of human sites, including the body's largest living organ, the skin, as well as the tongue, hair and nails.
'The skin has evolved to make terrestrial life possible. It protects people from harmful ultraviolet radiation and from viral, fungal, bacterial and chemical attack, as well as retaining moisture,' he said.
'Keratins form the cellular skeleton of keratinocytes, the most abundant cell type present in the epidermis, the outer layer of the skin.
'Keratinocytes undergo a process of progressive maturation called keratinisation in which newly formed kertatinocytes arise from the skin's basal layer and proceed to eventually become lifeless, flattened cells in the outer skin layer, the stratum corneum.
'In a healthy epidermis, these changes are tightly regulated, but a defect in any one of the structural components or enzymatic processes has the potential to disrupt this balance and cause disease.'
This was the case for a group of diseases classified as disorders of keratinization, including the ichthyoses, the follicular keratoses and the keratodermas.
Dr Rothnagel said mutations in keratins had been identified in a number of these disorders.
'For example, we have linked a mutation in a particular keratin with the skin disorder Pachyonychia congenita in a collaboration with Dr Paul Bowden at the University of Cardiff.
Patients with this hereditary condition typically suffer deformed fingernails caused by a keratotic scale growing underneath. Other symptoms can include calluses on the feet, tongue abnormalities, and even corneal abnormalities and precocious eruption of teeth in newly-born babies.
Dr Rothnagel said considerable progress had been made in identifying both disease-causing mutations and inconsequential changes that occurred in the epidermal keratins. The cumulative total to date was over 60 different mutations in more than 120 separate incidences of disease involving 18 different keratins.
His laboratory is taking a multi-pronged approach to studying the role of keratin. One research team is working in partnership with Professor Brandon Wainwright's group at the Centre for Molecular and Cellular Biology on the relationship between hair follicle development and the most common skin cancer type, basal cell carcinoma.
Other researchers in the group are identifying disease-causing mutations in patients with inherited skin disorders; examining keratin K6 isoforms in normal and diseased skin; elements and factors regulating keratin K6 transcription; and isolating and characterising novel keratins.
Dr Rothnagel said gene therapy applications offered long-term promise to ameliorate skin conditions.
'The rationale is that if we can solve some of the problems associated with rare diseases, we can use the paradigm to remedy more common disorders,' he said.
For further information, contact Dr Rothnagel, telephone 07 3365 4629 or 07 3365 4625; email: josephr@biosci.uq.edu.au
