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：
10889305
负责人：
JAMES F GUSELLA
金额：
$ 104.67万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10889305
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

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

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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在huntingtin（HTT）基因中的CAG重复道中的膨胀称为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份（年龄30至50岁），目前没有治疗以延迟发作或进展。对高清的弹性，这是一种现象，据此运动和认知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神经退行性疾病。但是，重大障碍限制了弹性机制的发现仅使用人类遗传学方法，因为高弹性个体很少见，并且不对称载体可能会逃避注意力或被神经科医生毫无分类。此外，不可能进行纵向分子分析人脑组织。 HD的动物模型为更易于处理的机会弹性机制的发现和表征，但它们并不能使我们能够确定控制人类弹性的特定基因和变体。这些局限性造成了至关重要的需求创新的方法来协同动物高清模型的力量与许多与医学相关的丰富人类数据。该提案的总体目的是确定对高清电机，认知和通过应用系统遗传学方法的生存特征，从而整合了高维分子数据具有相同菌株中收集的认知和病理数据的MHTT弹性的个体菌株纵向提供候选基因，然后对人类HD进行疾病修饰进行测试。对此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“人性化”小鼠种群中有助于HD弹性的修饰符（AIM 1）。网络方法将用于将这些新数据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）。最后，这些修饰符将通过深入进行验证新的精度HD模型上的神经生物学和行为表型（AIM 3）。这些研究将使发现和验证新的目标，用于促进健康的大脑整体衰老和对HD的抗韧性特别的。