Genetics of Alopecia Areata in the C3H/HeJ Mouse

描述(由申请人提供)： 斑秃是一种毁容的人类自身免疫性皮肤病，具有复杂的遗传基础，以活跃生长期的毛囊为靶标，通常与其他系统性自身免疫性疾病有关。脱发造成的心理创伤，特别是对十几岁的女孩来说，可能会非常严重，以至于导致自杀。再生障碍性贫血可在一生中的某个时间影响多达2%的总人口(600万美国公民)。C3H/HeJ小鼠自发发生AA，与人类一样，这是一种非常复杂的多基因疾病，与人类AA患者和大鼠AA模型具有共同的易感基因。我们先前的假设是由于免疫调节基因的相互作用，这些基因影响的通路可以通过对先前确定的每个数量性状基因(QTL)区间内的基因表达水平的系统分析来识别。虽然这个想法仍然可行，但我们现在已经在这些QTL中发现了超越免疫调节基因的基因，以解释这种极其复杂的疾病的发病机制中的许多关键问题。来自再生障碍性贫血横断面研究(包括自发性疾病小鼠)的基因阵列数据，当与4个再生障碍性贫血数量性状基因座(QTL)内所有基因的实时定量RT-PCR(QPCR)和基于全基因组测序的单倍型图谱数据(Sanger草案序列)相结合时，将被用来识别参与再生障碍性贫血发病机制的众多候选基因，从而为未来的干预试验确定分子通路的优先顺序。为了验证这项工作，我们将使用一个原型小鼠AA特定的QPCR384基因阵列(完成)来提供基于表达的表型能力，添加基于表达的数量性状基因座(EQTL)分析方法来分析新的遗传杂交。通过评估在协作交叉小鼠(近200个仔细进行基因分型的新小鼠品系，提供扩展的遗传多样性)单独老化过程中发生再生障碍性贫血的小鼠，我们将识别新的QTL并提炼已知的QTL。在这样做的过程中，我们将缩短小鼠的遗传间隔，寻找和测试候选基因，识别新的基因座，并验证我们的新分子工具，这些工具最终将增加药物和诊断筛选方法的价值。使用这种小鼠模型的发现继续有助于更好地理解和治疗人类再生障碍性贫血，特别是因为最近的人类遗传连锁研究发现与我们的小鼠模型中的遗传间隔相对应。 公共卫生相关性： 斑秃是一种相对常见的自身免疫性疾病(占总人口的2%，一生中有600多万人)，会造成严重的心理压力。我们的小鼠模型提供了对这种极其复杂的遗传病的全面了解。超过38个基因在主数量性状基因座上调控失调，这些数据加上3个次要基因座的基因，已经确定了导致这种细胞介导的自身免疫性皮肤病的主要分子网络。头发中的一种主要结构蛋白被发现下调，导致斑秃的脆弱和断裂，这是斑秃的临床表现。环境(饮食中的维生素A水平)对疾病严重程度的影响首先在小鼠身上发现，最近在人类患者中得到证实。这些观察结果的提炼和扩展将有助于我们了解斑秃的遗传基础。斑秃疾病进展相关基因网络的变化和药物疗效筛选研究的成败将为准确诊断人类疾病和预测最佳治疗方案提供新的工具。

DESCRIPTION (provided by applicant): Alopecia areata (AA) is a disfiguring human autoimmune skin disease with a complex genetic basis that targets hair follicles in the actively growing anagen phase and is often associated with other systemic autoimmune diseases. Psychogenic trauma due to hair loss, particularly for teen-aged girls, can be so serious as to lead to suicide. AA can affect up to 2% of the general population at some time during their lives (6,000,000 US citizens). C3H/HeJ mice spontaneously develop AA and, like in humans, this is a very complex polygenic disease with susceptibility loci in common with both human AA patients and the rat AA model. Our previous hypothesis was that AA was due to the interaction of immune-regulatory genes affecting pathways that can be identified by systematic analysis of gene expression levels within each quantitative trait locus (QTL) interval previously identified. While this idea remains viable, we have now identified genes within these QTLs which go beyond immune regulatory genes towards explaining many of the key issues in the pathogenesis of this extremely complicated disease. Gene array data from a cross sectional AA study (completed, including mice with spontaneous disease), when combined with quantitative real time RT PCR (QPCR) for all genes within each of the 4 AA quantitative trait loci (QTLs) and haplotype mapping data based on total genomic sequencing (Sanger draft sequences), will be used to identify numerous candidate genes involved in the pathogenesis of AA that will allow for prioritization of molecular pathways for future intervention trials. To validate this work we will use a prototype mouse AA-specific QPCR 384 gene array (completed) to provide expression based phenotyping capabilities, adding Expression-based Quantitative Trait Locus (EQTL) analytical methods to analyze new genetic crosses. By evaluating mice that develop AA in the separate aging of Collaborative Cross mice (nearly 200 carefully genotyped novel mouse strains that provide expanded genetic diversity), we will identify new QTLs and refine the known QTLs. In so doing, we will reduce the mouse genetic intervals, find and test candidate genes, identify new loci, and validate our new molecular tools that will eventually add value to drug and diagnostic screening approaches. Discoveries using this mouse model continue to contribute to a better understanding and treatment options for human AA, especially since recent human genetic linkage studies found corresponding genetic intervals to those in our mouse model. PUBLIC HEALTH RELEVANCE: Alopecia areata is a relatively common (up to 2% of the population, 6,000,000+ people, during their lifetime) autoimmune disease that causes severe psychological stress. Our mouse model provides a comprehensive understanding of this extremely complex genetic disease. Over 38 genes are dysregulated in the major quantitative trait locus and, with these data, plus that from the 3 minor loci, the major molecular network has been defined that leads to this cell mediated autoimmune skin disease. One of the major structural proteins in the hair was identified that is downregulated resulting in fragility and breakage, the clinical presentation of alopecia areata. Environmental (vitamin A levels in the diet) effects on disease severity were first identified in the mouse and recently confirmed in human patients. Refining and expanding these observations will help us understand the genetic basis of alopecia areata. Changes in gene networks associated with alopecia areata disease progression and success or failure of drug efficacy screening studies will provide new tools to accurately diagnose the human disease and predict optimal treatment regiments.