Genetics of Alopecia Areata in the C3H/HeJ Mouse

C3H/HeJ 小鼠斑秃的遗传学

• 批准号: 8506975
• 负责人: JOHN Paul SUNDBERG
• 金额: $ 36.21万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 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/8506975
• 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 Targeting; Failure; Future; Gene Expression; Gene Expression Profiling; 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; 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; screening; skin disorder; success; systemic autoimmune disease; tool

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）是一种具有复杂遗传基础的毁容性人类自身免疫性皮肤病，其靶向生长旺盛期的毛囊，并且通常与其他全身性自身免疫性疾病相关。由于脱发造成的心理创伤，特别是对十几岁的女孩来说，可能严重到导致自杀。AA可以影响高达2%的一般人口在他们的生活中的某个时候（6，000，000美国公民）。C3 H/HeJ小鼠自发地发展AA，并且与人类一样，这是一种非常复杂的多基因疾病，其易感基因座与人类AA患者和大鼠AA模型相同。我们以前的假设是，AA是由于免疫调节基因的相互作用影响的途径，可以通过系统分析的基因表达水平内的每个数量性状位点（QTL）的间隔以前确定。虽然这一想法仍然可行，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，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研究的基因阵列数据（已完成，包括患有自发性疾病的小鼠），当与4个AA数量性状基因座（QTL）中的每一个内的所有基因的定量真实的时间RT PCR（QPCR）和基于全基因组测序的单倍型作图数据相结合时（桑格草稿序列），将用于识别参与AA发病机制的众多候选基因，这将为未来的干预试验优先考虑分子途径。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。通过评估在协作杂交小鼠（近200种经过仔细基因分型的新型小鼠品系，提供了扩展的遗传多样性）的单独老化中发展AA的小鼠，我们将鉴定新的QTL并改进已知的QTL。通过这样做，我们将减少小鼠遗传间隔，发现和测试候选基因，鉴定新的基因座，并验证我们的新分子工具，最终为药物和诊断筛选方法增加价值。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AA的选择，特别是因为最近的人类遗传连锁研究发现了与我们的小鼠模型相应的遗传间隔。 公共卫生关系： 斑秃是一种相对常见的（高达2%的人口，6，000，000+人，在他们的一生中）自身免疫性疾病，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。超过38个基因在主要数量性状基因座中失调，并且利用这些数据，加上来自3个次要基因座的数据，已经定义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鉴定为下调，导致脆性和断裂，即斑秃的临床表现。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发现，最近在人类患者中得到证实。提炼和扩展这些观察结果将有助于我们了解斑秃的遗传基础。与斑秃疾病进展和药物疗效筛选研究的成功或失败相关的基因网络的变化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。