Genetic Mechanisms Controlling Resilience to Huntington's Disease

控制亨廷顿病抵抗力的遗传机制

基本信息

批准号：
10531136
负责人：
JAMES F GUSELLA
金额：
$ 12.32万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531136
关键词：
Age Alleles Alzheimer&apos 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 Dimensions Disease Disease model Emotional Exons Functional Imaging Genes Genetic Genetic Variation Genomic Segment Genotype Health Heterozygote Hippocampus Human Human Genetics Human Genome Huntington Disease Huntington gene Impaired cognition Individual Individual Differences Inherited Knock-in Knock-out Knockout Mice Length Link Longevity Maps 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 Predisposition Prefrontal Cortex Prevention Psyche structure Quantitative Trait Loci RNA Resolution Rest Severities Symptoms System Testing The Jackson Laboratory Transgenic Organisms Translating Validation Variant abnormal involuntary movement age related neurodegeneration aging brain autosome behavioral phenotyping brain tissue candidate validation cognitive function cohort gene interaction genetic approach genetic resource 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 resilience factor segregation structural imaging success synergism trait transcriptome sequencing translational model

项目摘要

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.

项目概要/摘要亨廷顿病（HD），一种由基因突变引起的常染色体显性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，其特征是异常不自主运动、严重智力衰退以及情绪变化，包括烦躁和抑郁。这些症状主要发生在黄金工作年龄（30至50岁），目前尚无发现。延缓 HD 发作或进展的治疗，HD 是一种运动和认知相关的现象。功能比基于基因型的预测要好，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。然而，重大障碍限制了恢复机制的发现。单独使用人类遗传方法，因为高复原力的个体很少见，而且无症状携带者可能会逃避注意或被神经科医生错误分类此外，不可能进行纵向行为。 HD 动物模型的分子分析为研究提供了更容易处理的机会。弹性机制的发现和表征，但它们本身并不能让我们识别控制人类恢复能力的特定基因和变异体对这些限制产生了迫切的需求。将动物 HD 模型的力量与丰富的医学相关知识相结合的创新方法该提案的总体目标是确定 HD 运动、认知和恢复能力的驱动因素。通过应用系统遗传学方法整合高维分子数据来确定生存特征单个菌株对 mHTT 有弹性，并在同一菌株中收集认知和病理数据纵向提供候选基因，然后对其进行人类 HD 疾病修饰测试。 end，一种新型小鼠面板，包含表达全长突变体的 mHTT 杂合敲入等位基因内源水平的亨廷顿蛋白，在遗传多样性的隔离背景（BXD 面板）上将生成的目的是识别有助于“人性化”小鼠群体 HD 恢复能力的修饰因子（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集成，以识别最后，这些修正将通过深入的执行来验证。新的精确 HD 模型的神经生物学和行为表型分析（目标 3）将成为可能。发现并验证了促进健康大脑整体老化和 HD 恢复能力的新靶点特别的。