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：
7982853
负责人：
JOHN Paul SUNDBERG
金额：
$ 41.7万
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/7982853
关键词：
A/J Mouse Adult Affect Age 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 Dideoxy Chain Termination DNA Sequencing 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 Life Link Lod Score 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 Work 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）：脱发Areata（AA）是一种具有复杂遗传基础的人类自身免疫性皮肤疾病的毁容，该遗传基础靶向积极生长的Anagen期，并且通常与其他全身性自身免疫性疾病有关。由于脱发而造成的心理创伤，尤其是对于十几岁的女孩而言，可能是如此严重，以至于导致自杀。 AA一生的某个时候（美国公民）的某个时候可能会影响多达2％的普通人群。 C3H/HEJ小鼠自发发展AA，与人类一样，这是一种非常复杂的多基因疾病，具有与人AA患者和大鼠AA模型共同的易感基因座。我们以前的假设是AA是由于影响途径的免疫调节基因的相互作用，可以通过对先前鉴定的每个定量性状基因座（QTL）间隔内的基因表达水平进行系统分析来识别。尽管这个想法仍然可行，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，可以解释这种极为复杂的疾病发病机理的许多关键问题。横截面AA研究的基因阵列数据（完成，包括患有自发疾病的小鼠），与定量实时RT PCR（QPCR）结合使用，用于4个AA定量性状基因座（QTLS）中的每个基因中的所有基因（QPCR）和基于单倍型映射数据的基因在总基因组测序（Sanger草稿序列）上，将用于确定与AA发病机理有关的众多候选基因，该基因将允许分子途径的优先级以进行将来的干预试验。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）提供基于表达的表型能力，从而增加了基于表达的定量性状基因座（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的单独衰老中开发AA的小鼠（近200个精心基因型的新型小鼠菌株，提供扩展的遗传多样性），我们将识别新的QTL并完善已知的QTL。这样，我们将减少小鼠遗传间隔，查找和测试候选基因，识别新的基因座并验证我们的新分子工具，最终将为药物和诊断筛查方法增加价值。使用这种小鼠模型的发现继续为人类AA的更好理解和治疗选择做出贡献，尤其是自最近的人类遗传连锁研究发现与小鼠模型中的遗传间隔相应的遗传间隔。公共卫生相关性： Areata脱发是一种相对常见的（最多2％的人口，一生中有6,000,000多人）自身免疫性疾病，会引起严重的心理压力。我们的小鼠模型对这种极其复杂的遗传疾病提供了全面的理解。超过38个基因在主要的定量性状基因座中失调，并且使用这些数据，从3个次要基因座中，已经定义了主要的分子网络，从而导致该细胞介导的自身免疫性皮肤疾病。鉴定出头发中的主要结构蛋白之一被下调，导致脆弱性和破裂，即Areata的临床表现。在小鼠中首先发现了对疾病严重程度的影响（饮食中的维生素A水平），并在人类患者中得到证实。精炼和扩展这些观察结果将有助于我们了解脱发的遗传基础。与脱发疾病进展以及药物疗效筛查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并预测最佳治疗方案提供新的工具。