Genetic Mechanisms Controlling Resilience to Huntington's Disease

控制亨廷顿病抵抗力​​的遗传机制

• 批准号: 10388685
• 负责人: JAMES F GUSELLA
• 金额: $ 106.35万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388685
• 关键词: Age; Alleles; Alzheimer' s Disease; Animal Model; Animals; Attention; Behavior; Brain; Brain region; CAG repeat; Candidate Disease Gene; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Corpus striatum structure; DNA; Data; Disease; Disease model; Emotional; Exons; Genes; Genetic; Genetic Variation; Genomic Segment; Genotype; Health; Hippocampus (Brain); Human; Human Genetics; Human Genome; Huntington Disease; Huntington gene; Image; Impaired cognition; Individual; Individual Differences; Inherited; Knock-in; Knock-out; Knockout Mice; Length; Link; Longevity; Mediating; Medical; Mental Depression; Methods; Modification; Molecular; Molecular Analysis; Motor; Motor Cortex; Mus; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neurodegenerative Disorders; Neurologist; Pathologic; Pathology; Patients; Population; Prefrontal Cortex; Prevention; Psyche structure; Quantitative Trait Loci; RNA; Resolution; Rest; Severities; Suggestion; Symptoms; System; Testing; The Jackson Laboratory; Transgenic Organisms; Translating; Validation; abnormal involuntary movement; age related neurodegeneration; aging brain; base; behavioral phenotyping; brain tissue; cognitive function; cohort; gene interaction; gene network; genetic approach; genetic resource; genetic variant; genome-wide; high dimensionality; human data; humanized mouse; innovation; insight; motor disorder; motor symptom; mouse genetics; mutant; nervous system disorder; neuropathology; new therapeutic target; novel; resilience; success; trait; transcriptome sequencing; translational model

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.

项目总结/摘要 亨廷顿氏病（HD）是一种常染色体显性遗传的神经退行性疾病， 亨廷顿蛋白（HTT）基因中CAG重复序列的扩增，称为mHTT，其特征是异常的 不自主运动，严重的智力下降，以及包括易怒和抑郁在内的情绪变化。 这些症状主要发生在黄金工作年龄（30至50岁），目前没有 治疗以延迟发作或进展。对HD的恢复力，一种运动和认知 功能比基于基因型的预测更好，部分原因是尚未确定的遗传因素。 这些因素可能为HD和其他年龄相关疾病的治疗和预防提供关键目标。 神经退行性疾病然而，重大障碍限制了复原力机制的发现 仅使用人类遗传学方法，因为高度适应性的个体很罕见， 可能会被神经科医生忽视或错误分类。此外，不可能进行纵向 对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， 恢复机制的发现和表征，但它们本身并不能让我们确定 特定的基因和变异体来控制人类的适应力。这些限制造成了对以下方面的迫切需要： 创新的方法，以协同动物HD模型的力量与丰富的医学相关的 人类数据。本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，整合来自以下的高维分子数据， 个体菌株对mHTT具有弹性，在相同菌株中收集认知和病理数据 以纵向提供候选基因，然后测试其在人HD中的疾病修饰。本 末端，一种新的小鼠组，其包含表达全长突变体的mHTT杂合敲入等位基因 亨廷顿蛋白在内源性水平，在遗传多样性的分离背景（BXD面板）将是 产生了用于鉴定在“人源化”小鼠群体中有助于HD恢复力的修饰剂（Aim 1）。 网络方法将用于将这些新数据与现有的人类HD数据整合，以识别 人类HD恢复力的调节剂（目标2）。最后，将通过执行深入的 神经生物学和行为表型的新的精确HD模型（目的3）。这些研究将使 发现和验证新的目标，以促进健康的大脑老化的整体和弹性，以HD 特别的。