SUMMARY OF RESEARCH BEING UNDERTAKEN

This project is the continuation of work undertaken by Prof. McGrath with the aid of funding from the Barbara Ward Children’s Foundation. Kindler syndrome is a hereditary condition in the EB family of genetic conditions. This gene defect causes skin blistering in childhood and there is considerable clinical overlap between Kindler syndrome and dystrophic EB, in that these disorders share features such as friction induced blistering, webbing of the fingers and toes, difficulty in swallowing and urethral narrowing. Later in life, Kindler syndrome patients have thinning and premature ageing of the skin; abnormal skin pigmentation; and extreme sensitivity to sunlight.

The previous work by Prof. McGrath identified the gene causing Kindler syndrome, which makes a protein named kindlin-1. This new protein has features that are consistent with functions involved in maintaining the structure of the skin and of communication between cells. How the loss of this protein causes skin blistering and other features of Kindler syndrome is not fully understood and needs to be studied in more detail using animal models. Furthermore, such animal models will be needed to develop gene therapy for the condition.

It is proposed to make a mouse model with a modified genetic make up, using established genetic technology. The kindlin-1 gene will be "knocked out" in one strain of modified mice to produce animals genetically equivalent to Kindler syndrome patients. In addition, a second strain of modified mice will be made where the kindlin-1 gene can be "knocked out" in precise areas of the skin by the application of a drug. This system has recently been used to produce the most useful mouse models of EB simplex so far developed. (This EB simplex work, involving collaboration between Dundee and Houston, is also funded by DebRA UK and the National Institutes of Heath in the USA has just agreed a grant of $1,750,000 to take over when the DebRA grant finishes.)

These animal models will allow us to study the mechanism of skin blistering and other features of Kindler syndrome in detail and are also a necessary resource for gene therapy development.

The applicants have successfully applied to the Medical Research Council for funding of the salary of a highly qualified Clinical Research Fellow, leaving the costs of materials and the mice for funding by DebRA.