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Discovering Novel Gene Networks for Skin Diseases

发现皮肤病的新基因网络

基本信息

批准号：
8582268
负责人：
JOHN Paul SUNDBERG
金额：
$ 19.2万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8582268
关键词：
Affect Aging Animal Model Award Biological Models Biological Process Biology Clinical Computer software Cutaneous Data Disease Disease model Embryo Evaluation Expert Opinion Freezing Gene Proteins Gene Silencing Generations Genes Genetic Genotype Goals Grant Histologic Histology Histopathology Homologous Gene Human Image Immunohistochemistry Informatics Institutes International Knock-out Knockout Mice Knowledge Lesion Life Ligands Lipids Methodology Methods Molecular Morbidity - disease rate Mus Mutant Strains Mice Mutate Nature Organ Outcome Pathogenesis Pathologist Pathway Analysis Pathway interactions Phenocopy Phenotype Physicians Physiological Proteins Protocols documentation Public Health Recording of previous events Recurrence Research Research Personnel Resources Scientist Site Visit Skin Slide Specimen Staining method Stains Teleconferences The Jackson Laboratory Time Translations Trust United States National Institutes of Health Work aged base cohort embryonic stem cell experience gene discovery gene function human disease insight interest mouse genome mouse model mutant novel programs public health relevance receptor screening skills skin disorder skin lesion tool web site

项目摘要

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.

描述（由申请人提供）：传统方法一次识别一种疾病特异性基因（所谓的正向遗传学），然后找出分子发病机制。这种方法是劳动密集型的、昂贵的、缓慢的，并且质量由研究者的技能和关注的兴趣来定义（限制）。因此，分析仍然不全面，方法也不标准化。国际基因敲除小鼠计划（KOMP 2）将系统地产生所有已知基因的突变小鼠，这些基因的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。当前的表型分析项目提供了有关各种生理功能的信息，但没有提供具体的组织学变化信息，特别是与人类皮肤疾病相关的信息。这是全球许多大规模表型分析项目中反复出现的问题。皮肤是少数只能通过肉眼（临床）和组织病理学检查进行正确评估的器官之一。我们之前已经证明，经验丰富的组织病理学家/基础科学家，尤其是具有皮肤疾病专业知识的科学家，可以快速筛选大量标本并将结果整合到动物模型/基因发现计划中。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，该方法比非集中表型筛选方法具有优势。这样，与人类皮肤疾病直接相关的新见解和发现将迅速出现。我们将通过以下方式实现我们的目标：1）系统地筛选 KOMP 2 突变小鼠的皮肤病变； 2) 将突变小鼠与人类皮肤组织病理学的已知疾病进行比较； 3）将新的表型信息整合到已知的基因网络中。总而言之，我们的综合方法将通过定义单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。