Dr. Stella Man, from the Institute of Cell and Molecular Sciences, Queen Mary's University, London, UK, said that the discovery may have implications for the treatment of a wide range of wounds, including post-surgery.
Dr. Man and her team, led by Professor David Kelsell, were studying the association between a mutation of a gene (GJB2) which produces a protein called Cx26 which is the most common cause of genetic deafness. Professor Kelsell was the first to describe the link between Cx26 mutations and deafness in 1997. "Since many people carry this mutation", Dr. Man said, "and people who have just one such mutation are not deaf, we felt that there might be some evolutionary advantage to it, so we decided to investigate how the mutation affected the ability of cells to communicate with each other in the epidermis where Cx26 is also expressed."
The cells within tissues such as skin need to be able to communicate with each other in order to retain their correct characteristics and allow the tissue to grow and repair itself. One way that cells communicate is through the regulated opening and closing of channels called gap junctions that link cells together. The main components of these channels are proteins called connexins, of which Cx26 is one.
"When we looked at the function of Cx26 in a laboratory skin model", said Dr. Man, "we found that it was directly associated with wound healing and bacterial invasion. We concluded that there is a definite advantage to carrying a mutation in this protein."
If a drug that temporarily knocks out Cx26 protein can be successfully delivered to the wound, healing could be improved. Such a drug could be useful in a wide range of epidermal wounds, she said. The scientists now intend to test the effect of Cx26 mutation in other epithelial cell types, such as the gut, where defence against infection is also important.
"It is interesting to speculate that Cx26 deafness mutations have been selected over the evolutionary process due to their beneficial effects on wound healing," said Dr. Man.
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They then applied their approach to HALP, a gene naturally active in T cells. Dr. Finkel previously discovered and named HALP, an acronym for "HIV-associated life preserver," showing that it had a role in prolonging HIV infection by helping HIV-infected T cells survive attack by the immune system.
Using siRNA and their laboratory techniques, the investigators succeeded in "knocking down," that is, decreasing gene expression by HALP. Because their previous research strongly suggests that HALP promotes latent HIV infection, the new technique has a potential application to HIV treatment. "The siRNA may represent a suicide vector: by knocking down HALP it may allow HIV-infected cells to self-destruct, thus eliminating a hiding place for the virus," said Dr. Finkel.
"More broadly," she added, "the technique could theoretically be directed against other immune-related diseases, by silencing harmful genes active in T cells."
Dr. Finkel's co-authors, all from The Children's Hospital of Philadelphia, were Jiyi Yin, Ph.D., Zhengyu Ma, Nithianandan Selliah, Ph.D., Debra K. Shivers and Randy Q. Cron, M.D., Ph.D. National Institutes of Health grants supported the research, along with support from the University of Pennsylvania Center for AIDS Research and the University's Cancer Center, the Bender Foundation, the Joseph Lee Hollander Chair at The Children's Hospital of Philadelphia, and the W. W. Smith Charitable Trust.
"Effective Gene Suppression Using Small Interfering RNA in Hard-to-Transfect Human T Cells." Journal of Immunological Methods. In press, published online March 24, 2006.
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