Discovering Novel Gene Networks for Skin Diseases

描述（由申请人提供）：传统方法一次鉴定一个疾病特异性基因（所谓的正向遗传学），然后确定分子发病机制。这种方法是劳动密集型的，昂贵的，缓慢的，质量是由调查员的技能和集中的兴趣定义（有限）。因此，分析仍然不全面，方法也不标准。国际敲除小鼠计划（KOMP 2）将系统地产生所有已知基因的突变小鼠，其功能在很大程度上是未知的。这种方法为发现影响正常皮肤功能的单个基因失活提供了前所未有的机会。目前的表型分析项目提供了各种生理功能的信息，但没有具体的组织学变化，特别是与人类皮肤疾病的相关性。这在世界范围内的许多大规模表型分型项目中一直是一个反复出现的问题。皮肤是少数几个只能通过大体（临床）和组织病理学检查进行适当评价的器官之一。我们以前已经表明，一个有经验的组织病理学家/基础科学家，特别是一个皮肤疾病的专业知识，可以快速筛选大量的标本，并将结果整合到一个动物模型/基因发现计划。这种方法通过将相似的皮肤组织病理学分类为不同的表型组并将基因特异性表型整合到已知的基因网络中，比非聚焦表型筛选方法具有优势。在这样做的过程中，新的见解和发现将以快速的速度出现，与人类皮肤病直接相关。我们将通过以下方式实现我们的目标：1）以系统的方式筛选KOMP 2突变小鼠的皮肤病变; 2）比较突变小鼠与人类皮肤组织病理学的已知疾病; 3）将新的表型信息整合到已知的基因网络中。总而言之，我们全面的方法将通过定义单个基因突变引起的疾病，迅速扩展我们对正常皮肤生物学分子机制的知识和研究工具。

DESCRIPTION (provided by applicant): 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.