Genetics of Alopecia Areata in the C3H/HeJ Mouse

C3H/HeJ 小鼠斑秃的遗传学

基本信息

批准号：
8111044
负责人：
JOHN Paul SUNDBERG
金额：
$ 38.12万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111044
关键词：
A/J Mouse Adult Affect Aging Alleles Alopecia Areata Alternative Splicing Autoimmune Diseases Autoimmune Process C3H/HeJ Mouse Candidate Disease Gene Cells Chromosome Mapping Clinical Code Complex Computer software Congenic Strain Consomic Strain Data Databases Diagnosis Diagnostic Diet Disease Disease Progression Drug Delivery Systems Failure Future Gene Expression General Population Genes Genetic Genetic Crosses Genetic Variation Genomics Genotype Hair Hair follicle structure Haplotypes Hereditary Disease Human Human Genetics Immune Inbred Strain Intervention Trial Knock-out Lead Link Maps Mediating Minor Modeling Molecular Mouse Strains Mus Mutate Northern Blotting Nucleic Acid Regulatory Sequences Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Polygenic Traits Population Predisposition Psychological Stress Public Health Quantitative Trait Loci Rattus Regulator Genes Resistance Resources Screening procedure Severities Severity of illness Structural Protein Suicide Technology Teenagers Testing Time Transcript Trauma Vitamin A Western Blotting Work aged analytical method base design drug efficacy genetic linkage girls human disease mouse model mutant novel prototype public health relevance repository skin disorder success systemic autoimmune disease tool

项目摘要

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.

描述（由申请人提供）：斑秃 (AA) 是一种毁容性人类自身免疫性皮肤病，具有复杂的遗传基础，其目标是处于活跃生长期的毛囊，并且通常与其他系统性自身免疫性疾病相关。脱发造成的心理创伤，特别是对于十几岁的女孩来说，可能会严重到导致自杀。 AA 可能会影响高达 2% 的普通人群一生中的某个时间（6,000,000 名美国公民）。 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，其易感位点与人类 AA 患者和大鼠 AA 模型相同。我们之前的假设是，AA 是由于影响途径的免疫调节基因的相互作用所致，这些途径可以通过对先前确定的每个数量性状基因座 (QTL) 区间内的基因表达水平进行系统分析来确定。虽然这个想法仍然可行，但我们现在已经确定了这些 QTL 中的基因，这些基因超越了免疫调节基因，可以解释这种极其复杂的疾病发病机制中的许多关键问题。来自横断面 AA 研究（已完成，包括患有自发性疾病的小鼠）的基因阵列数据，结合 4 个 AA 数量性状基因座 (QTL) 中每个基因的定量实时 RT PCR (QPCR) 和基于单倍型作图数据全基因组测序（桑格草案序列）将用于识别与 AA 发病机制相关的众多候选基因，从而为未来的干预试验确定分子途径的优先顺序。为了验证这项工作，我们将使用原型小鼠 AA 特异性 QPCR 384 基因阵列（已完成）来提供基于表达的表型分析功能，并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。通过评估在单独老化的协作杂交小鼠（近 200 个经过仔细基因分型的新型小鼠品系，提供扩展的遗传多样性）中产生 AA 的小鼠，我们将鉴定新的 QTL 并完善已知的 QTL。在此过程中，我们将减少小鼠遗传区间，寻找和测试候选基因，识别新基因座，并验证我们的新分子工具，最终将为药物和诊断筛选方法增加价值。使用该小鼠模型的发现继续有助于更好地理解人类 AA 和治疗方案，特别是最近的人类遗传连锁研究发现了与我们的小鼠模型中的相应的遗传间隔。公共卫生相关性：斑秃是一种相对常见的自身免疫性疾病（一生中发病率高达 2%，即 6,000,000 多人），会导致严重的心理压力。我们的小鼠模型提供了对这种极其复杂的遗传疾病的全面了解。主要数量性状基因座中有超过 38 个基因失调，根据这些数据，加上 3 个次要基因座的数据，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，导致头发脆弱和断裂，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中被发现，最近在人类患者中得到证实。完善和扩展这些观察结果将有助于我们了解斑秃的遗传基础。与斑秃疾病进展相关的基因网络变化以及药效筛选研究的成功或失败将为准确诊断人类疾病和预测最佳治疗方案提供新工具。