Recently, Prof. McLean’s group discovered the genetic defect that causes a condition known as LOC syndrome- a specific form of junctional EB. In LOC syndrome patients have a chronic defect in wound healing – they continually produce a type of abnormal tissue, called granulation tissue, in their skin, eyes, mouth, throat and other sites. Granulation tissue is also a problem in other types of EB and in more common conditions, including rheumatoid arthritis, leg ulcers and so on. There is no effective drug at the present time specifically to treat granulation tissue in any of these conditions.

Most LOC patients are lacking a small piece of protein found in the skin known as laminin alpha-3a. Complete loss of laminin alpha-3a causes the severe Herlitz type of junctional EB and loss of this small part of the protein causes LOC. Recently, the group identified one LOC patient with a different type of mutation also affecting this same small part of the laminin alpha-3a protein. This is strong evidence that this region of the laminin alpha-3a protein, which is called the N domain, is a key signal that turns off granulation tissue production at the end of the wound healing process. In LOC patients this signal is absent and so granulation tissue continues to be made continuously. This discovery is very exciting because it tells us for the first time how granualation tissue production is turned off in the skin after a wound is healed and it also opens the way to develop drugs to accelerate this process. This project builds on the discovery towards identifying such drugs.

Firstly, a range of agents will be made to study the No-domain under experimental conditions. Secondly, the effect of the N-domain or parts of it will be studied on cells that are found in granulation tissue. We know that cells called fibroblasts are likely to be the main culprits in producing granulation tissue so we will focus on these, but will also look at other types of cell, just in case. The effect of the N-domain on the attachment, growth, migration and death of these human cells in culture will be studied. It is thought that one way the N-domain might work is to trigger the death of certain cells at the end of wound healing. We know that cells die off at this time but no-one knows what tells these cells that their job is done and it’s time to die. We suspect that the N-domain is this signal.

Once the effect of the N-domain on cultured cells is established and we know which type of cell is the main target for its activity, we will analyse these cells to see what type of protein the N-domain binds to trigger this effect. This protein will be known as the N-domain receptor. Once we identify the N-domain receptor, we can develop a system to look for drugs that bind strongly to the N-domain receptor and therefore mimic the effect of the N-domain.

In Dundee medical school, we have access to a newly opened £1million laboratory dedicated to drug discovery. We will use this facility to screen 32,000 chemical compounds to find those that bind to the N-domain receptor. When we find a potential chemical that does what we want, we can access an additional 500-1000 subtle variations of that chemical that might work even better, get into skin more easily and have less side-effects etc. We also have access to a bigger set of 500,000 test compounds through a collaboration with Prof. Sir David Lane.