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.

项目摘要/摘要 亨廷顿氏病（HD），一种由突变引起的常染色体显性神经退行性疾病 CAG重复素（HTT）基因的膨胀称为MHTT，以异常为特征 非自愿运动，严重的精神下降以及情绪变化，包括烦躁和抑郁。 症状主要发生在主要工作年度（年龄在30至50岁之间），Ando目前没有 延迟发作或进展的治疗。 功能比基于基因型的预测更好，部分是由于尚未确定的遗传因素。 这些因素可能为治疗和预防高清和其他年龄有关的关键目标提供 但是，神经退行性疾病。 仅使用人类遗传学方法，因为高弹性个体很少见，无症状的载体 可能会逃避阶级或被神经病学分类。 对人体组织的分子分析。 弹性机制的发现和表征，但并非自己允许我们识别您 这些局限性的特定基因和变体产生了关键 具有与大量医疗相关的动物高清模型的力量的创新方法 人类数据的总体目标是确定对高清电机，认知和 通过应用系统遗传学方法来整合来自高维分子数据的生存特征 具有认知和病理数据收集器中的MHTT弹性的个体菌株在相同的菌株中 纵向为候选基因提供了对人类HD的疾病修饰的测试 结束的新型小鼠面板结合了表达全长突变体的MHTT杂合敲击等位基因 在遗传多样性（BXD面板）的隔离背景下，内源水平的亨廷顿蛋白将是 生成的旨在确定在小鼠种群中有助于HD弹性的修饰修饰符（AIM 1）。 网络方法将用于将它们与现有的人类高清数据集成在一起以识别 人类高清弹性的修饰符（AIM 2）。 新的精度HD模型上的神经生物学和行为表型（AIM 3）。 在促进健康的大脑衰老和对高清弹性的新型目标的发现和验证 特别的。