Huntington's Disease Repeat Instability and Pathogenesis

亨廷顿病重复不稳定和发病机制

基本信息

批准号：
8448749
负责人：
VANESSA C WHEELER
金额：
$ 35.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8448749
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 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 screening stem therapeutic target

项目摘要

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.

描述（由申请人提供）：亨廷顿氏病（HD）是一种毁灭性的致命神经退行性疾病，这是由HD基因中多态CAG重复膨胀引起的，它触发细胞死亡，对纹状体和皮质中神经元的特异性触发。尽管从15年前发现了潜在的遗传突变，但尽管为了解导致神经变性的分子途径而进行了广泛的努力，但仍无法治愈或有效治疗。近年来，显而易见的是，HD CAG重复突变会发生急剧组织特异性的体细胞扩张，特别是在疾病中受影响的大脑区域。这提出了一个假设，即靶组织的体细胞HD CAG长度增加有助于HD发病机理。我们在过去的融资周期中产生的数据既是在精确的HDH CAG敲击HD的HD小鼠模型和HD个体的死后大脑中的数据，这强烈支持了这一假设，这意味着改变体细胞不稳定的因素也可能是疾病的修饰者。在这里，我们提出了实验以阐明进一步的a）导致体细胞不稳定性和HD发病机理的因素，b）体细胞不稳定性与疾病表型的关系。在AIM 1中，我们将确定并表征遗传变异体的遗传变异，这些变体是体细胞不稳定性差异的基础，以及在两个近交遗传背景上，先天性HDH CAG敲入小鼠菌株之间早期表型的差异。在AIM 2中，我们将将HDH CAG敲入小鼠跨越小鼠背景（MSH3 - / - ），该背景没有显示体细胞不稳定性，并确定对行为表型和晚期病理学的影响。在AIM 3中，我们将量化大量高清尸体后大脑中的体细胞不稳定性，并对HD患者的体细胞不稳定性的修饰剂进行全基因组关联研究。我们还将研究来自HD患者的诱导多能茎（IPS）细胞的神经元的不稳定性，目的是产生不稳定性细胞培养模型，以替代人类不稳定性的筛查。这些研究将共同洞悉导致体细胞不稳定性和HD致病过程的因素。这将基于攻击DNA突变本身的策略，导致HD和其他三核苷酸重复疾病的新型治疗靶标。