Naturally Occurring Dog Model for Juvenile Dermatomyositis

描述(由申请人提供)： 幼年皮肌炎自然发生犬模型。青春期皮肌炎(DM)发病的遗传因素尚不清楚。青少年DM以皮疹和进行性肌肉无力为特征，是儿童遗传性炎症性肌病中最常见的一种。这项建议的长期目标是促进发现与人类糖尿病发展有关的遗传因素。家犬的一种自发性炎症性肌病，也称为皮肌炎，在临床、组织学和免疫学上与人类幼年糖尿病相似，是该疾病的唯一动物模型。狗为研究复杂的特征提供了许多优势。狗的品种是遗传隔离的种群，每个品种都经历了创始人效应、种群瓶颈和/或流行的父系效应，导致了显著的同质性。与人类家庭相比，大胎次和短妊娠期产生的减数分裂信息要多得多，而且与其他模式生物不同，狗与我们共享环境，有高水平的医学监测，并定期接受疫苗接种。这些因素既增加了遗传性异常被识别的可能性，同时也增强了它们与人类健康的相关性。这项建议的总体目标是利用狗模型的同质性来识别影响糖尿病发展的遗传因素。这里的假设是，狗的DM是由多个具有强烈影响的基因座控制的，并且基于我们自己的初步数据，以及对犬自身免疫性疾病遗传学的其他研究结果。这一假设将通过追求两个具体目标来检验：1)确定与犬皮肌炎相关的基因组区域；2)研究狗第二类白细胞抗原(DLA)与皮肌炎的相关性。在第一个目标下，一个由127,000个SNPs组成的小组将在受DM影响的设得兰牧羊犬和对照设得兰牧羊犬中进行基因分型，并用于病例/对照分析，以确定与犬DM相关的基因组区域。在第二个目标下，将确定DLA II类基因座DRB1、DQA1和DQB1的三个基因座单倍型，并评估其与犬DM的相关性。众所周知，AIM 1中使用的SNP小组对DLA区域的覆盖较差，因此必须单独检查。这两个目标在申请人手中都被确定为可行的。这项拟议的研究将确定在糖尿病犬模型中对疾病发病起重要作用的遗传因素，并提供可能在人类形式的糖尿病疾病发展中发挥作用的候选基因。这种方法是创新的，因为它利用了一种自然发生的狗疾病模型，以更好地了解导致糖尿病的复杂遗传因素。

DESCRIPTION (provided by applicant): Naturally occurring dog model for juvenile dermatomyositis. The genetic factors contributing to the development of juvenile dermatomyositis (DM) are poorly defined. Juvenile DM, characterized by a skin rash and progressive muscle weakness, is the most common of the inherited childhood inflammatory myopathies. The long-term goal of this proposal is to facilitate the discovery of genetic factors involved in the development of DM in human populations. A spontaneous, inflammatory myopathy of domestic dogs, also termed dermatomyositis, is clinically, histologically, and immunologically similar to human juvenile DM, and is the only animal model for the disease. Dogs offer numerous advantages for the study of complex traits. Dog breeds are genetically isolated populations, each of which has experienced founder effects, population bottlenecks, and/or popular sire effects, resulting in significant homogeneity. Large litter sizes and a short gestational period yield many more informative meiosis than do human families, and unlike other model organisms, dogs share our environment, have a high level of medical surveillance, and receive regular vaccinations. These factors both enhance the probability that inherited abnormalities will be recognized, and at the same time, enhance their relevance to human health. The overall objective of this proposal is to exploit the homogeneity of the dog model to identify genetic factors that influence the development of DM. The hypothesis here is that DM in dogs is governed by multiple loci with strong effects, and is based on both our own preliminary data, and findings from other investigations into the genetics of canine autoimmune diseases. This hypothesis will be tested by pursuing two specific aims: 1) identify genomic regions associated with canine dermatomyositis, and 2) investigate class II dog leukocyte antigens (DLA) for association with dermatomyositis. Under the first aim, a panel of 127,000 SNPs will be genotyped in DM- affected and control Shetland sheepdogs and used in a case/control analysis to identify genomic regions associated with canine DM. Under the second aim, three-locus haplotypes will be determined for the DLA class II loci, DRB1, DQA1, and DQB1, and assessed for association with DM in dogs. The DLA region is known to be poorly covered by the SNP panel used in Aim 1 and thus must be examined separately. Both aims have been established as feasible in the applicant's hands. The proposed research will identify genetic factors that are important to disease pathogenesis in a dog model for DM and provide candidate genes that may play a role in disease development in human forms of DM. This approach is innovative because it utilizes a naturally occurring dog model of disease to better understand the complex genetic factors that contribute to DM.