Novel mouse genetic models to study modifiers of Huntington’s disease

研究亨廷顿舞蹈病修饰因子的新型小鼠遗传模型

基本信息

批准号：
10210455
负责人：
Xiangdong William Yang
金额：
$ 64.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210455
关键词：
Address Affect Age Age of Onset Alleles Bacterial Artificial Chromosomes Behavior Behavioral Brain CAG repeat Cells Cessation of life Chiroptera Corpus striatum structure DNA DNA Damage DNA Interstrand Cross-Link Repair DNA Repair Enzymes DNA Repair Pathway Defect Disease Electrophysiology (science)Environmental Risk Factor Exhibits Fanconi&apos s Anemia Fragile X Syndrome Functional disorder Future Gene Dosage Genes Genetic Genetic Models Genetic Transcription Genomics Human Human Genetics Huntington Disease Huntington gene Inherited Investigation Knock-in Knock-in Mouse Length MLH1 gene MSH3 gene Mediating Mismatch Repair Modeling Modification Molecular Mosses Motor Activity Mus Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Nuclear Inclusion Onset of illness Other Genetics PMS1 gene PMS2 gene Pathogenesis Pathologic Pathology Pathway interactions Patients Phenotype Physiological Regulation Resources Role Series Severity of illness Signal Transduction Sleep disturbances Testing Therapeutic Tissues Transgenic Mice Trinucleotide Repeat Expansion Trinucleotide Repeats United States Variant base behavioral impairment cohort disease phenotype experience gene repair genome wide association study genomic locus in vivo innovation interest knock-down molecular phenotype motor symptom mouse genetics mouse model mutant novel nuclease polyglutamine prevent protective allele protein complex psychiatric symptom response transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Huntington's disease (HD) is one of the most common autosomal dominant neurodegenerative disorders affecting 30,000 patients in the US. HD patients typically experience motor, cognitive and psychiatric symptoms, which is associated with the loss of the striatal and cortical neurons. The disease inexorably progresses after the onset and patients typically succumb to the disease about 10-20 years after disease onset. HD is caused by a CAG repeat expansion, that encodes a polyglutamine repeat, in mutant Huntingtin (mHTT). Currently, there is no treatment to prevent the onset or slow the progression of HD. A recent genome wide association study (GWAS) identified several loci associated with modification of HD age of disease onset. The most significant loci identified were in Chr. 15 and encompasses a DNA repair enzyme called FAN1. Interestingly, FAN1 and two other genes identified in the HD modifier GWAS (MLH1 and MSH3) are all implicated in the instability of mHTT CAG repeat in somatic tissues. However, it is unclear whether FAN1's roles in CAG repeat instability is related to its function as a modifier of HD pathology including behavioral impairment (locomotor activity, sleep disturbance), striatal and cortical neuronal electrophysiological and pathological changes, and transcriptional dysregulation. In this proposal, we will address these critical questions using two HD mouse models, the Q140 murine Htt knockin model and a novel human genomic BAC transgenic mouse model of HD with >120 pure CAG repeats. The latter model is the first human mHTT model that shows CAG repeat instability that is correlated with behavioral deficits, and robust striatum-selective transcriptional dysregulation. We will cross these two HD mouse models with novel Fan1/FAN1 genetic models to address the following key questions: 1. Does reducing endogenous murine Fan1 levels accelerate the pathogenesis in the two HD mouse models (Aim 1)? 2. Do mice with murine Fan1-R510H knockin alleles (equivalent to the human patient-derived, deleterious FAN1 variant R507H) show disease-exacerbating effects, similar to the Fan1 knockdown mice (Aim 2)? and 3. Whether genetic mouse models with elevated expression of human FAN1 (BAC-FAN1) can ameliorate the behavioral, electrophysiological, pathological and molecular (i.e. transcriptomic) phenotypes in the two HD mouse models (Aim 3)? The findings from our study will be crucial to unravel where in the brain and what molecular mechanisms underly how Fan1 mutants modify HD pathogenesis in vivo. Furthermore, the mouse resources we have developed and the phenotyping platforms that will use in this study will be invaluable to future investigations of other HD modifiers and for developing therapeutics to target the HD human genetic modifiers to prevent, slow or stop progression of HD.

项目概要亨廷顿病 (HD) 是最常见的常染色体显性神经退行性疾病之一影响美国 30,000 名患者。 HD 患者通常会出现运动、认知和精神方面的问题症状，这与纹状体和皮质神经元的丧失有关。疾病来势汹汹发病后病情进展，患者通常在发病后约 10-20 年死亡发病。 HD 是由突变亨廷顿蛋白中编码聚谷氨酰胺重复序列的 CAG 重复序列扩展引起的（mHTT）。目前，尚无治疗方法可以预防 HD 的发生或减缓 HD 的进展。最近的一项全基因组关联研究 (GWAS) 确定了与 HD 年龄改变相关的几个位点疾病发作。确定的最重要的位点位于 Chr。 15 并包含 DNA 修复酶称为 FAN1。有趣的是，FAN1 和 HD 修饰符 GWAS 中发现的其他两个基因（MLH1 和 MSH3）都与体组织中 mHTT CAG 重复的不稳定性有关。但目前还不清楚是否 FAN1 在 CAG 重复不稳定性中的作用与其作为 HD 病理学调节剂的功能有关，包括行为障碍（运动活动、睡眠障碍）、纹状体和皮质神经元电生理学和病理变化以及转录失调。在本提案中，我们将使用两种 HD 鼠标模型（Q140 鼠 Htt）来解决这些关键问题敲入模型和新型人类基因组 BAC 转基因小鼠 HD 模型，具有 >120 个纯 CAG 重复序列。后一个模型是第一个显示 CAG 重复不稳定性的人类 mHTT 模型，该不稳定性与行为缺陷和强大的纹状体选择性转录失调。我们将跨越这两个高清具有新型 Fan1/FAN1 遗传模型的小鼠模型可解决以下关键问题： 1. 是否减少内源性小鼠 Fan1 水平会加速两种 HD 小鼠模型的发病机制（目标 1）？ 2. 做具有鼠 Fan1-R510H 敲入等位基因（相当于人类患者来源的有害 FAN1）的小鼠变体 R507H）显示出疾病恶化效应，类似于 Fan1 敲低小鼠（目标 2）？和 3. 人类 FAN1 (BAC-FAN1) 表达升高的基因小鼠模型是否可以改善两种 HD 中的行为、电生理、病理和分子（即转录组）表型鼠标模型（目标 3）？我们的研究结果对于揭示大脑的位置以及分子机制至关重要揭示了 Fan1 突变体如何改变体内 HD 发病机制。此外，我们拥有的鼠标资源开发的和本研究中将使用的表型平台对于未来的研究具有无价的价值其他 HD 修饰剂以及开发针对 HD 人类基因修饰剂的治疗方法，以预防、减缓或停止 HD 的进展。