Alopecia and Ulcerative Dermatitis in B6 Mice

B6 小鼠的脱发和溃疡性皮炎

基本信息

批准号：
7230185
负责人：
JOHN Paul SUNDBERG
金额：
$ 22.63万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-20 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230185
关键词：
Address Affect African American Alcohol dehydrogenase Alopecia Backcrossings Binding Proteins Binding Sites Biochemical Genetics Biomedical Research Breeding Chronic Cicatrix Clinical Comb animal structure Communities Complex Data Dermatitis Diagnosis Diet Disease Disease susceptibility Drug Metabolic Detoxication Enzymes Family member Female Figs - dietary Frequencies Future Genes Genetic Genome Goals Grant Grooming Hereditary Disease Histologic Histopathology Housing Human In Vitro Inbred Strain Laboratories Laboratory Animals Lesion Life Style Maps Metabolism Molecular Profiling Monitor Mus Oxidoreductase Pathogenesis Pathway interactions Patients Pattern Phenotype Polymerase Chain Reaction Proteins Quantitative Trait Loci Research Resistance Resources Retinal Retinal dehydrogenase Retinoic Acid Binding Retinoids Rodent Role Series Services Severities Skin Susceptibility Gene Syndrome Synthetic Diet Testing Thinking Time Toxic effect Tretinoin Vitamin A Woman Work base comparative human disease in vivo insight mouse model outcome forecast oxidation simple sequence length polymorphism skin disorder trait

Address Affect African American Alcohol dehydrogenase Alopecia Backcrossings Binding Proteins Binding Sites Biochemical Genetics Biomedical Research Breeding Chronic Cicatrix Clinical Comb animal structure Communities Complex Data Dermatitis Diagnosis Diet Disease Disease susceptibility Drug Metabolic Detoxication Enzymes Family member Female Figs - dietary Frequencies Future Genes Genetic Genome Goals Grant Grooming Hereditary Disease Histologic Histopathology Housing Human In Vitro Inbred Strain Laboratories Laboratory Animals Lesion Life Style Maps Metabolism Molecular Profiling Monitor Mus Oxidoreductase Pathogenesis Pathway interactions Patients Pattern Phenotype Polymerase Chain Reaction Proteins Quantitative Trait Loci Research Resistance Resources Retinal Retinal dehydrogenase Retinoic Acid Binding Retinoids Rodent Role Series Services Severities Skin Susceptibility Gene Syndrome Synthetic Diet Testing Thinking Time Toxic effect Tretinoin Vitamin A Woman Work base comparative human disease in vivo insight mouse model outcome forecast oxidation simple sequence length polymorphism skin disorder trait

展开

项目摘要

DESCRIPTION (provided by applicant): Central centrifugal cicatricial alopecia (CCCA) in humans was once thought to be a grooming disorder primarily affecting black women called "hot comb alopecia". More recently, CCCA is considered to be a primary disease, formerly called "follicular degeneration syndrome" and currently CCCA. Little is known about the pathogenesis of this disfiguring human disease. Mouse models of many human skin diseases exist. A strain specific disease called B6 alopecia, B6 dermatitis, or chronic ulcerative dermatitis is a major biomedical research resource problem that is clinically and histologically essentially identical to CCCA and affects primarily black female mice, particularly C57BL/6J (B6). We will refine the comparative observations, initiate studies to determine if this mouse disease has a genetic basis, and test the hypothesis that abnormal metabolism of vitamin A may be 1 of the underlying mechanisms. Many genes have retinoic acid binding sites that form part of a regulatory complex. Oxidation of retinal to retinoic acid occurs through the action of several retinal dehydrogenases, 2 of which (Aldh1a2 and Aldh1a3) are differentially expressed in B6 mice compared to other common inbred strains. B6 mice are naturally hypomorphic for alcohol dehydrogenase 4 (Adh4), which may be involved in detoxifying vitamin A metabolites resulting in these enzyme expression pattern changes where CCCA lesions begin. Dehydrogenase/reductase SDR family member 9 (Dhrs9) protein levels are upregulated in B6 substrains with high alopecia frequency further producting retinoic acid. Dhrs9 is downregulated in those with low alopecia frequency. Rodent diets high in vitamin A may complicate this situation. We will test this hypothesis by evaluating expression of these and other genes in B6 and closely related substrains given synthetic diets with defined levels of vitamin A. Results of these studies will help modify breeding and colony management of B6 mice to eliminate or minimize any impact of B6 dermatitis on research. Future work will apply findings to human patients to either modify lifestyle or more appropriately treat CCCA to reduce suffering and disfiguration.

描述（由申请人提供）：人类中的中央离心丝网膜脱发（CCCA）曾经被认为是一种主要影响黑人妇女的美容障碍，称为“热梳脱发”。最近，CCCA被认为是一种原发性疾病，以前称为“卵泡变性综合征”和目前CCCA。关于这种毁容人类疾病的发病机理知之甚少。存在许多人类皮肤疾病的小鼠模型。一种称为B6脱发，B6皮炎或慢性溃疡性皮炎的菌株特异性疾病是一个主要的生物医学研究资源问题，在临床和组织学上与CCCA基本相同，主要影响黑人雌性小鼠，尤其是C57BL/6J（B6）。我们将完善比较观察结果，开始研究以确定该小鼠疾病是否具有遗传基础，并检验以下假设：维生素A的异常代谢可能是基本机制中的1个。许多基因具有构成调节复合物一部分的视黄酸结合位点。视网膜到视网膜酸的氧化是通过几种视网膜脱氢酶的作用发生的，其中2种（ALDH1A2和ALDH1A3）在B6小鼠中与其他常见的近交菌株相比在B6小鼠中差异表达。 B6小鼠是醇脱氢酶4（ADH4）的自然型肌，这可能参与排毒维生素A代谢物，从而导致CCCA病变开始的情况下这些酶表达模式变化。脱氢酶/还原酶SDR家族成员9（DHRS9）蛋白水平在具有较高脱发频率进一步产生视黄酸的B6底座中上调。 DHRS9在脱发频率较低的人中被下调。啮齿动物饮食高维生素A可能会使这种情况变得复杂。我们将通过评估具有定义水平的维生素A的合成饮食中这些和密切相关的底物的表达来检验该假设。这些研究的结果将有助于改变B6小鼠的繁殖和菌落管理，以消除或最大程度地减少B6皮炎对研究的任何影响。未来的工作将对人类患者进行调查，以修改生活方式或更适当地治疗CCCA以减少痛苦和毁容。