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：
7237199
负责人：
VANESSA C WHEELER
金额：
$ 36.73万
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 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7237199
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 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 Process Prosencephalon Relative (related person)Research Research Design Research Personnel Role Role playing therapy Severity of illness Stretching System Testing Therapeutic Tissues Transgenes Translating Whole Organism disease phenotype genetic association human Huntingtin protein insight intergenerational mouse model mutant mutation carrier novel polyglutamine programs promoter recombinase research study size tool

项目摘要

DESCRIPTION (provided by applicant): 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 DNA 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.

描述（由申请人提供）：亨廷顿氏病（HD）是一种致命的神经退行性疾病，这是由于多态CAG重复术的扩展，超出了约36个单位的阈值。扩展的CAG重复被转化为亨廷汀蛋白氨基末端的聚谷氨酰胺伸展，从而在纹状体和皮质中的神经元子集中触发细胞死亡。扩展的CAG重复还在种系和体细胞组织中表现出巨大的不稳定性。这项研究的长期目标是阐明HD CAG重复重复不稳定的分子途径以及突变亨廷顿蛋白触发的特定神经变性。在准确概括人HD突变的HD敲击小鼠中，MSH2基因是重复不稳定性和早期纹状体表型的修饰符。在这项研究中，我们将测试MSH2在不匹配修复途径中起作用的假设，以改变HD敲入小鼠的CAG重复不稳定性和早期表型。我们将与缺乏特定的不匹配修复基因的小鼠和携带MSH2 ATPase域突变的小鼠进行遗传杂交。这些实验将为MSH2在CAG重复不稳定性和突变HD等位基因的表型表达中的作用提供机械洞察力。为了确定候选DNA修复基因是否是人类遗传关联研究年龄的修饰者，将使用偏离CAG重复大小预测的值的“极端”个体进行研究。为了进一步了解MSH2修饰小鼠中重复不稳定性和早期纹状体疾病的机制，我们将使用CRE-LoxP系统产生MSH2基因的条件敲除。我们将使用CAMKLLA驱动的CRE转基因在前脑神经元中特异性灭活MSH2，以测试MSH2在纹状体神经元中作用以修饰不稳定性和早期表型的假设。这些研究将共同洞悉重复不稳定性和发病机理的机制，从而导致旨在减慢或停止这种毁灭性疾病的理性治疗策略。