Traditional approaches identify one disease-specific gene (so-called forward genetics) at a time and then work out the molecular pathogenesis. This approach is labor intensive, expensive, slow, and the quality is defined (limited) by the investigator's skills and focused interests. Therefore, the analysis remains incomprehensive and the methods non-standardized. The International Knockout Mouse Program (KOMP 2) will systematically generate mutant mice for all known genes, the function(s) of which are largely unknown. This approach provides an unprecedented opportunity to discover a single gene inactivation affecting normal skin function. The current phenotyping projects provide information on a variety of physiological functions but nothing specifically on histologic changes especially with correlation to human skin disorders. This has been a recurrent problem in many of the large-scale phenotyping projects worldwide. The skin is one of the few organs that can only be properly evaluated by gross (clinical) and histopathological examination. We have previously shown that an experienced histopathologist/basic scientist, especially one with expertise on cutaneous disorders, could rapidly screen large numbers of specimens and integrate the results into an animal model/gene discovery program. This approach provides an advantage over non-focused phenotypic screening approaches by classifying similar cutaneous histopathology into distinct phenotypic groups and by integrating the gene-specific phenotypes into known gene networks. In so doing, new insights and discoveries will be forthcoming at a rapid pace with direct correlation to human skin disorders. We will accomplish our goal by: 1) screening KOMP 2 mutant mice for skin lesions in a systematic fashion;2) comparing mutant mouse with human cutaneous histopathology for known disorders;and 3) integrating new phenotypic information into known gene networks. Altogether, our comprehensive methodology will rapidly expand our knowledge and research tools on the molecular mechanisms of normal skin biology through defining diseases caused when single genes are mutated.
While the burden of morbidity that skin diseases cause in the USA is nearly 1/3 of all conditions that called for evaluation by a physician, genotypes with phenotype annotations of mouse genetic based skin disease models are extremely poorly annotated for the mouse, i.e. a dismal 6.5%. Technological advances have now made it possible to generate targeted gene inactivation of all known genes in the mouse genome. An international effort to knockout all known genes, the International Knockout Mouse Project (KOMP 1), set out to generate embryonic stem (ES) cells to be developed into live mice (KOMP 2). Our proposal is relevant to public health in regards to skin disorders because our comprehensive approach aims at correlating genotype to phenotype (skin disease). By doing so, we will match a human skin disease to the mouse homolog providing novel insight(s) into its molecular pathogenesis. !
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