Alopecia and Ulcerative Dermatitis in B6 Mice

点击翻译按钮获取中文摘要

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.