Ultraviolet B (UVB, 29O-320nm), a component of natural sunlight, causes a selective immunosuppression which appears to be a critical risk factor for UV carcinogenesis and which may impact on the course of certain infectious diseases. We have identified in mice a genetically determined susceptibility to immunosuppression by UVB and have developed a model for autosomal and X-linked genetic control of susceptibility to UV immunosuppression.
Our specific aims are directed toward confirmation of this model and identification and cloning of the genes responsible. Our strategy is to approach this question using genetically defined strains of mice to define the parameters of the in vivo phenotype and to characterize gene action by techniques of molecular biology. The combination of these two approaches is necessary to understanding control of UV suppression at the phenotypic level and at the molecular level. We have produced a congenic strain for one of the autosomal genes which has enabled us to isolate the action of this gene for high and low susceptibility to UV immunosuppression and will permit its identification and cloning Establishment of genetic linkage is a necessary prerequisite to gene identification for this complex phenotype.
The specific aims are l) testing of the model for genetic control of susceptibility to UV immunosuppression, 2) complete derivation and testing of a strain of mice congenic for a major dominant autosomal gene regulating high susceptibility to UV immunosuppression, 3) establish genetic linkage of the major dominant autosome gene and 4) identify the autosomal gene using Differential Display cloning. Cloning and sequencing the genes controlling UV suppression will enable identification of homologous loci in the human genome. Further, our unique finding of genetic control of UV suppression by autosomal and X- linked genes can be used as a model for testing for similar control mechanisms in humans. A genetically determined high susceptibility to the immunosuppressive effects of Uv radiation may be a highly significant risk factor for a significant number of human diseases.
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