Huntington's Disease Repeat Instability and Pathogenesis

亨廷顿病重复不稳定和发病机制

• 批准号: 8244952
• 负责人: VANESSA C WHEELER
• 金额: $ 37.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244952
• 关键词: Affect; Age; Attenuated; Autopsy; Behavioral; Biological Assay; Brain; Brain region; CAG repeat; Cell Culture Techniques; Cell Death; Cells; Chromosome Mapping; Cognitive; Collection; Confidential Information; Corpus striatum structure; Data; Discrimination; Disease; Emotional; Evaluation; Event; Funding; Gene Mutation; Genes; Genetic; Genotype; Government; Haplotypes; Health Care Costs; Human; Huntington Disease; Inbreeding; Individual; Inherited; Knock-in Mouse; Knockout Mice; Lead; Length; Long-Term Care; Malignant Neoplasms; Mediating; Mismatch Repair; Modeling; Molecular; Motor; Mouse Strains; Mus; Mutation; Natural History; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Nuclear; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phenotype; Process; Quantitative Trait Loci; Sampling; Screening procedure; Social Discrimination; Specificity; Staging; Stem cells; Symptoms; Testing; Therapeutic Intervention; Tissues; Trinucleotide Repeats; Variant; Zinc Fingers; base; congenic; disease phenotype; effective therapy; genetic variant; genome wide association study; genome-wide; human Huntingtin protein; induced pluripotent stem cell; insight; interest; mouse model; mutant; new therapeutic target; novel; novel strategies; nuclease; public health relevance; research study; stem; therapeutic target

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HD gene that triggers cell death with a specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 15 years ago, there is still no cure or effective treatment despite extensive efforts to understand the molecular pathways that lead to neurodegeneration. In recent years it has become apparent that the HD CAG repeat mutation undergoes dramatic tissue-specific somatic expansion, particularly in the brain regions affected in the disorder. This raises the hypothesis that somatic HD CAG length increases in target tissues contribute to HD pathogenesis. Data that we have generated during the past funding cycle both in accurate genetic Hdh CAG knock-in mouse models of HD and in postmortem brain from HD individuals strongly support this hypothesis, implying that factors that modify somatic instability may also be modifiers of disease. Here we propose experiments to elucidate further a) the factors that contribute to somatic instability and HD pathogenesis, and b) the relationship of somatic instability to disease phenotypes. In Aim 1 we will identify and characterize the genetic variants that underlie the difference in somatic instability and the difference in an early phenotype between congenic Hdh CAG knock-in mouse strains on two inbred genetic backgrounds. In Aim 2 we will cross Hdh CAG knock-in mice onto a mouse background (Msh3-/-) that displays no somatic instability and determine the effect on behavioral phenotypes and late-stage pathology. In Aim 3 we will quantify somatic instability in a large collection of HD postmortem brains and perform a genome-wide association study for modifiers of somatic instability in HD patients. We will also investigate instability in neurons derived from induced pluripotent stem (iPS) cells from HD patients with the aim of generating a cell culture model of instability as an alternative to screen for modifiers of instability in humans. Together, these studies will provide insight into the factors that contribute to somatic instability and the HD pathogenic process. This will lead to novel therapeutic targets both for HD and other trinucleotide repeat diseases based upon a strategy of attacking the DNA mutation itself. PUBLIC HEALTH RELEVANCE: Huntington's disease is a devastating, fatal neurodegenerative disorder for which there is no cure or effective treatment. The combination of emotional, cognitive and motor symptoms, leading to long-term care needs results in an extremely high healthcare cost, estimated at 25 billion dollars a year. This study is aimed at identifying early modifiers of disease with the potential of discovering novel targets for early therapeutic intervention.

描述（由申请人提供）：亨廷顿病（HD）是一种毁灭性的致命性神经退行性疾病，由 HD 基因中多态性 CAG 重复序列的扩增引起，该重复序列会特异性地针对纹状体和皮质中的神经元触发细胞死亡。尽管15年前就发现了潜在的基因突变，但尽管人们付出了大量努力来了解导致神经退行性变的分子途径，但仍然没有治愈或有效的治疗方法。近年来，越来越明显的是，HD CAG 重复突变经历了显着的组织特异性体细胞扩张，特别是在受该疾病影响的大脑区域。这提出了这样的假设：靶组织中体细胞 HD CAG 长度的增加有助于 HD 发病机制。我们在过去的资助周期中在 HD 的精确基因 Hdh CAG 敲入小鼠模型和 HD 个体死后大脑中获得的数据强烈支持这一假设，这意味着改变体细胞不稳定性的因素也可能是疾病的调节因素。在这里，我们提出实验来进一步阐明a）导致躯体不稳定和HD发病机制的因素，以及b）躯体不稳定与疾病表型的关系。在目标 1 中，我们将鉴定和表征两种近交遗传背景下同源 Hdh CAG 敲入小鼠品系之间体细胞不稳定性差异和早期表型差异背后的遗传变异。在目标 2 中，我们将 Hdh CAG 敲入小鼠与不表现出体细胞不稳定性的小鼠背景 (Msh3-/-) 杂交，并确定对行为表型和晚期病理学的影响。在目标 3 中，我们将量化大量 HD 死后大脑中的体细胞不稳定性，并对 HD 患者体细胞不稳定性的修饰因素进行全基因组关联研究。我们还将研究来自 HD 患者的诱导多能干 (iPS) 细胞的神经元的不稳定性，目的是生成不稳定性的细胞培养模型，作为筛选人类不稳定性修饰因子的替代方案。总之，这些研究将深入了解导致躯体不稳定和 HD 致病过程的因素。这将基于攻击 DNA 突变本身的策略，为 HD 和其他三核苷酸重复疾病带来新的治疗靶点。 公共健康相关性：亨廷顿舞蹈症是一种毁灭性、致命的神经退行性疾病，无法治愈或有效治疗。情绪、认知和运动症状的结合导致了长期护理需求，导致医疗费用极高，估计每年高达 250 亿美元。这项研究旨在确定疾病的早期调节因素，并有可能发现早期治疗干预的新靶点。