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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：
7848408
负责人：
VANESSA C WHEELER
金额：
$ 0.93万
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848408
关键词：
ATPase Domain Age Age of Onset Alleles Behavior Breeding CAG repeat Candidate Disease Gene Cell Death Corpus striatum structure Cyclic AMP DNA Repair DNA Repair Gene Disease Disease Marker Event Exhibits Genes Genetic Genetic Crosses Genetic Variation Genomics Goals Home environment Homologous Gene Human Human Genetics Huntington Disease Individual Investigation Knock-in Mouse Knock-out Length Microsatellite Repeats Mismatch Repair Molecular Mus Mutant Strains Mice Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nucleotides Pathogenesis Pathway interactions Patients Phenotype Play Process Prosencephalon Relative (related person)Research Research Design Research Personnel Role Severity of illness Stretching System Testing Therapeutic Tissues Transgenes Translating Whole Organism disease phenotype gene repair genetic association human Huntingtin protein insight intergenerational mouse model mutant mutation carrier novel polyglutamine programs promoter recombinase research study tool

项目摘要

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat tract beyond a threshold of ~ 36 units. The expanded CAG repeat is translated into a polyglutamine stretch at the amino-terminus of the huntingtin protein, triggering cell death in a subset of neurons in the striatum and cortex. The expanded CAG repeat also exhibits dramatic instability in the germline and in somatic tissues. The long-term goals of this research are to elucidate the molecular pathways that underlie the instability of the HD CAG repeat and the specific neurodegeneration triggered by mutant huntingtin. In HD knock-in mice, which accurately recapitulate the human HD mutation, the Msh2 gene is a modifier of repeat instability and an early striatal phenotype. In this study we will test the hypothesis that Msh2 acts in the mismatch repair pathway to modify CAG repeat instability and early phenotypes in HD knock-in mice. We will perform genetic crosses with mice deficient in specific mismatch repair genes and mouse line carrying a mutation in Msh2's ATPase domain. These experiments will provide mechanistic insight into Msh2's role in CAG repeat instability and phenotypic expression of the mutant HD allele. To determine whether candidate DMA repair genes are modifiers of the age of onset of HD in humans genetic association studies will be performed using 'extreme' individuals with onset ages deviating from values predicted by CAG repeat size. To gain further insight into the mechanism by which Msh2 modifies repeat instability and early striatal disease in the mouse we will generate a conditional knockout of the Msh2 gene using the Cre-loxP system. We will specifically inactivate Msh2 in forebrain neurons using a Camklla- driven Cre transgene to test the hypothesis that Msh2 acts in striatal neurons to modify instability and early phenotypes. Together, these studies will provide insight into mechanisms of repeat instability and pathogenesis, leading to rational therapeutic strategies aimed at slowing or halting this devastating disease.

亨廷顿氏病（HD）是一种致命的神经退行性疾病， CAG重复序列超过约36个单位的阈值。扩增的CAG重复序列被翻译成多聚谷氨酰胺在亨廷顿蛋白的氨基末端延伸，引发细胞死亡的一个子集，纹状体和皮层的神经元。扩增的CAG重复序列也表现出显著的不稳定性，生殖系和体细胞组织中。这项研究的长期目标是阐明导致HD CAG重复不稳定的途径和由HD CAG重复引发的特定神经退行性变突变亨廷顿蛋白在准确再现人类HD突变的HD基因敲入小鼠中，Msh 2 基因是重复不稳定性和早期纹状体表型的修饰物。在这项研究中，我们将测试假设Msh 2在错配修复途径中起作用以改变CAG重复序列的不稳定性和早期 HD基因敲入小鼠中的表型。我们将用缺乏特异性错配的小鼠进行遗传杂交，修复基因和Msh 2的ATP酶结构域中携带突变的小鼠品系。这些实验将提供 Msh 2在突变型HD的CAG重复不稳定性和表型表达中的作用的机制洞察等位基因确定候选DMA修复基因是否是人类HD发病年龄的调节因子遗传关联研究将使用发病年龄偏离通过CAG重复大小预测的值。为了进一步了解Msh 2修饰重复不稳定和早期纹状体疾病的小鼠，我们将产生Msh 2的条件性敲除。使用Cre-loxP系统的基因。我们将使用Camklla- 驱动的Cre转基因来测试Msh 2在纹状体神经元中起作用以改变不稳定性和早期表型总之，这些研究将提供深入了解重复不稳定性的机制，发病机制，导致合理的治疗策略，旨在减缓或停止这种毁灭性的疾病。