The Foundation's Research Grant Program is pleased to announce the funding of three worthy research projects:
Maurice van Steensel, MD PhD and Michel van Geel, MD, from University Hospital Maastricht, the Netherlands were awarded $50.000 for the project called "A Mouse Model for Keratitis-Ichthyosis-Deafness Syndrome."
Mason Freeman, MD, from Harvard Medical School in Boston, MA, was awarded $75,000 for his project titled "A Null Mouse Model of the Lamellar/Harlequin Ichthyosis ABCA12 Transporter."
Robert Rice, MD, from the University of California, Davis was funded $25,000 for his project "Proteomic Analysis of Ichthyosis: LI/CIE Focus."
Drs. van Steensel and van Geel summarized their project.
Keratitis-Ichthyosis-Deafness (KID) syndrome is a rare genetic disease characterized by severe ichthyosis, keratitis (inflammation of the cornea) leading to blindness and deafness. People with KID syndrome are also more sensitive to skin infections and can even develop skin cancer. This severe disease is caused by mutations in the protein connexin26, which is part of specialized communication channels between cells called gap junctions. After several years of research, we know that mutations in connexin26 can cause a range skin disorders, some similar to KID syndrome but most quite distinct. The reason for this diversity is not understood because we have a very limited view of what gap junctions do in the skin. As a consequence, we have no good treatment for our patients. In addition, it is difficult to study gap junction disorders of the skin because they are so rare. To remedy this situation, we decided to develop a mouse model for KID syndrome. To do this, we transfer a human connexin26 gene with a KID syndrome mutation into mouse embryo cells. Because we are interested in the ichthyosis that patients with KID syndrome develop, we use modern transgene technology to make a mouse that develops skin abnormalities but not the keratitis or the deafness. We also make sure that the disease gene is inducible, which means that it only becomes manifest when the animal is given an antibiotic. This approach reduces animal discomfort. Because we can switch the disease gene on and off at will, we can examine whether the skin disease is reversible. If it is, that means that patients might benefit from cutting-edge treatments that prevent the mutant protein from being made. Finally, we have constructed the transgene is such a way, that we can easily exchange the disease gene for another one so that we, or other groups, may study other types of ichthyosis.
We are excited that the F.I.R.S.T. is funding the development of our mouse model and we have begun the process of making mutant embryos. If all goes well, we will soon have a versatile model in which to study a severe form of ichthyosis and its treatment.
Dr. Mason Freeman is pleased to share his work with our F.I.R.S.T. members.
In our laboratory at the Massachusetts General Hospital, we have spent most of the past twenty years studying the role of cellular proteins that move lipids into or out of cells. Lipids are fats and are not dissolvable in water, so cells have developed special mechanisms for moving them around inside cells, as well as from inside a cell to outside a cell. One of the mechanisms cells use for this activity is a class of proteins called ABC transporters. ABC stands for ATP Binding Cassette. These transporters are proteins that bind the energy molecule of all cells, called ATP, and use its energy to move lipid molecules wherever the cell wants them to go. Both Lamellar Ichthyosis and Harlequin Ichthyosis have been associated with alterations in the gene encoding one of these ABC transporters, ABCA12. We recently generated mice in which the ABCA12 gene was deleted, and these mice share many of the same features that children with Harlequin Ichthyosis have. The mice have thickened skin and water evaporates through this skin much faster than normal. We used our many years of experience measuring different lipids to identify a defect in the skin of these mice and we discovered a very unusual and specific lipid to be missing. This result makes us think that the activity of ABCA12 that is missing, in children with the scaly skin problems linked to the ABCA12 transporter, must cause the special lipid we identified not to get to its appropriate location in the cell. This failure means that it does not get processed to the final, correct form needed to make the skin look and work normally. In the work that F.I.R.S.T. is funding us to perform, we will try to understand if this idea is correct and if there are any ways to correct the defect or re-supply the missing critical lipid. We are very excited about this work and grateful for the support of the Foundation. Most importantly, we want to help find better ways to treat those who have developed these very serious skin disorders.
Dr. Bob Rice explains his project.
A frequent problem in diagnosis and treatment of the ichthyoses is to understand the molecular basis for the severity of the disease. Patients with the same genetic diagnosis, for example, may suffer a range of severities. This project investigates whether variations in the proteins expressed in the epidermis can help explain the variation in severity. To determine which proteins are present, epidermal scale is digested with a protease that produces specific protein fragments that are then analyzed by mass spectrometry. Preliminary results indicate that more than 50 proteins can be identified in this way and that samples from several ichthyosis patients show deficiencies in certain proteins. Building on this information, the present work will examine more samples and look for characteristic deficiencies. It will also seek more quantitative information on variations in levels of targeted proteins known or suspected of contributing to differences in severity. This information may also assist in monitoring or designing therapies.
