Huntington's Disease Repeat Instability and Pathogenesis

亨廷顿病重复不稳定和发病机制

• 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
• 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

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.

亨廷顿病(HD)是一种致命的神经退行性疾病，由多态的 CAG重复区超过~36个单位的阈值。扩展的CAG重复序列被翻译成 聚谷氨酰胺在亨廷顿蛋白的氨基末端伸展，触发细胞死亡的一个子集 纹状体和皮质中的神经元。扩增的CAG重复序列也显示出显著的不稳定性 生殖系和体细胞组织中。这项研究的长期目标是阐明分子 HD CAG重复序列的不稳定性及其引发的特异性神经退行性变的通路 变种人亨廷顿。在HD敲入小鼠中，准确地概括了人类HD突变，Msh2 基因是重复不稳定的修饰物，是纹状体的早期表型。在这项研究中，我们将测试 假设Msh2在错配修复途径中作用于修改CAG重复序列的不稳定性和早期 HD敲入小鼠的表型。我们将与特定错配缺陷的小鼠进行基因杂交 修复基因和携带Msh2‘S ATPase结构域突变的小鼠品系。这些实验将提供 Msh2‘S在CAG重复序列不稳定性和突变型HD表型表达中作用的机制研究 等位基因。确定候选的DMA修复基因是否是人类HD发病年龄的修饰者 基因关联研究将使用发病年龄偏离 CAG重复大小预测的值。为了进一步了解Msh2修饰的机制 在小鼠反复出现不稳定和早期纹状体疾病时，我们将产生有条件的Msh2基因敲除 使用Cre-loxP系统。我们将使用Camclla来特地灭活前脑神经元中的Msh2- 驱动Cre转基因以验证Msh2作用于纹状体神经元以改变不稳定和早期的假说 表型。总而言之，这些研究将提供对重复不稳定和 导致合理的治疗策略，旨在减缓或阻止这种毁灭性的疾病。