Genetic Mechanisms Controlling Resilience to Huntington's Disease

项目摘要/摘要 亨廷顿病(HD)，一种常染色体显性遗传性神经退行性疾病，由一种突变引起 亨廷顿蛋白(Htt)基因CAG重复区段的扩展被称为mhtt，其特征是异常 不自主运动，严重的精神衰退，以及情绪变化，包括易怒和抑郁。 这些症状主要发生在黄金工作年龄段(30岁至50岁)，目前没有 延缓发病或进展的治疗。对HD的恢复力，一种运动和认知 功能比基于基因的预测更好，部分原因是尚未确定的遗传因素。 这些因素可能为HD和其他与年龄相关的疾病的治疗和预防提供关键目标 神经退行性疾病。然而，重大障碍限制了对弹性机制的发现 单独使用人类遗传方法是因为高弹性的个体是罕见的，并且是无症状的携带者 可能会逃脱注意或被神经科医生错误分类。此外，不可能进行纵向 人脑组织的分子分析。HD的动物模型提供了一个更容易处理的机会 弹性机制的发现和表征，但它们本身并不允许我们识别 控制人类韧性的特定基因和变种。这些限制导致对以下方面的迫切需求 将动物HD模型的力量与丰富的医学相关技术相结合的创新方法 人类数据。这项提案的总体目标是确定HD运动、认知和 通过应用系统遗传学方法整合来自 对mHTT有抵抗力的个体菌株，认知和病理数据收集在相同的菌株中 在纵向上提供候选基因，然后在人类HD中进行疾病修改测试。对这件事 一种结合了mHTT杂合敲入等位基因表达全长突变的新型小鼠面板 在内源水平上，在分离的遗传多样性背景上狩猎(BXD专家小组)将是 生成的目的是确定有助于在人性化的小鼠群体中恢复HD的修饰物(目标1)。 将使用网络方法将这些新数据与现有的人类高清数据相集成，以识别 人类HD复原力的修饰物(目标2)。最后，将通过深入执行来验证这些修饰符 新的精密HD模型的神经生物学和行为表型分析(目标3)。这些研究将使 新靶点的发现和验证可全面促进健康的脑老化和对HD的适应能力 很特别。

PROJECT SUMMARY/ABSTRACT Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder caused by a mutational expansion in a CAG repeat tract in the huntingtin (HTT) gene, termed mHTT, is characterized by abnormal involuntary movements, a severe mental decline, and emotional changes including irritability and depression. The symptoms primarily occur during prime working years (ages of 30 to 50), and there is currently no treatment to delay onset or progression. Resilience to HD, a phenomenon whereby motor and cognitive functioning is better than predicted based on genotype, is due in part to as-yet-unidentified genetic factors. These factors may provide key targets for treatment and prevention of HD and other age-related neurodegenerative diseases. However, significant barriers limit discovery of the mechanisms of resilience using human genetic methods alone because highly resilient individuals are rare, and asymptomatic carriers may escape attention or be misclassified by neurologists. Further, it is not possible to conduct longitudinal molecular analyses on human brain tissues. Animal models of HD provide a more tractable opportunity for discovery and characterization of resilience mechanisms, but they do not on their own allow us to identify the specific genes and variants that govern resilience in humans. These limitations create a critical need for innovative approaches to synergize the power of animal HD models with the wealth of medically relevant human data. The overall objective of this proposal is to identify drivers of resilience to HD motor, cognitive and survival traits by applying system genetics approaches that integrate high-dimensional molecular data from individual strains resilient to mHTT with cognitive and pathologic data collected in the same strains longitudinally to provide candidate genes that are then tested for disease modification in human HD. To this end, a novel mouse panel that incorporates a mHTT heterozygous knock-in allele expressing full-length mutant huntingtin at endogenous levels, on a segregated background of genetic diversity (BXD panel) will be generated to identify modifiers that contribute to HD resilience in a ‘humanized’ mouse population (Aim 1). Network approaches will be used to integrate these novel data with existing human HD data to identify modifiers of human HD resilience (Aim 2). Finally, these modifiers will be validated by performing in-depth neurobiological and behavioral phenotyping on new precision HD models (Aim 3). These studies will enable the discovery and validation of novel targets for promoting healthy brain aging overall and resilience to HD in particular.