Alopecia and Ulcerative Dermatitis in B6 Mice

B6 小鼠的脱发和溃疡性皮炎

• 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
• 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

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）：人类中心性离心性瘢痕性脱发（CCCA）曾被认为是一种主要影响黑人女性的梳洗障碍，称为“热梳性脱发”。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”，现在称为CCCA。人们对这种使人毁容的疾病的发病机制知之甚少。许多人类皮肤病的小鼠模型已经存在。一种被称为B6秃发、B6皮炎或慢性溃疡性皮炎的菌株特异性疾病是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，主要影响黑色雌性小鼠，特别是C57BL/6J （B6）。我们将完善比较观察，启动研究以确定这种小鼠疾病是否具有遗传基础，并测试维生素a代谢异常可能是潜在机制之一的假设。许多基因都有维甲酸结合位点，形成调控复合体的一部分。视网膜氧化为视黄酸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小鼠中与其他常见近交系相比表达不同。B6小鼠的酒精脱氢酶4 （Adh4）自然是低形态的，这可能与解毒维生素A代谢物有关，导致CCCA病变开始时这些酶的表达模式发生变化。脱氢酶/还原酶SDR家族成员9 （Dhrs9）蛋白水平在高脱发频率的B6亚株中上调，进一步产生维甲酸。在脱发频率低的人群中，Dhrs9表达下调。富含维生素A的啮齿动物饮食可能会使这种情况复杂化。我们将通过在给定维生素a水平的合成饲料中评估B6及其密切相关的亚菌株中这些和其他基因的表达来验证这一假设。这些研究结果将有助于改进B6小鼠的繁殖和菌落管理，以消除或尽量减少B6皮炎对研究的任何影响。未来的工作将把这些发现应用于人类患者，以改变生活方式或更适当地治疗CCCA，以减少痛苦和毁容。