Huntington's disease repeat instability and pathogenesis

亨廷顿病重复不稳定性和发病机制

基本信息

批准号：
9027108
负责人：
VANESSA C WHEELER
金额：
$ 58.97万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027108
关键词：
Affect Age Age of Onset Autopsy Brain Brain region CAG repeat Cell Death Cell Lineage Cells Chromosomes, Human, Pair 3 Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Corpus striatum structure DNA Repair DNA Repair Gene DNA Repair Pathway DNA Sequence Alteration Data Disease Emotional Enhancers Exhibits Gene Expression Gene-Modified Generations Genes Genetic Genetic Variation Genotype Guide RNA Health Care Costs Human Human Genome Huntington Disease Inherited Knock-in Mouse Length Liver Long-Term Care MLH1 gene Mediating MicroRNAs Mismatch Repair Modification Molecular Motor Mus Mutation Neurodegenerative Disorders Neurons Nuclear Onset of illness Outcome Pathogenesis Pathway interactions Patients Phenotype Process Rad30 protein Recruitment Activity Role Source Specificity Symptoms Testing Therapeutic Intervention Time Tissues Variant adeno-associated viral vector base disease phenotype effective therapy endonuclease genetic approach genome wide association study human Huntingtin protein human data in vivo induced pluripotent stem cell insight intergenerational knock-down lymphoblastoid cell line mouse model mutant novel public health relevance research study therapeutic development therapeutic target transmission process

项目摘要

DESCRIPTION (provided by applicant) Huntington's disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HTT gene that triggers cell death with a specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 20 years ago, there is still no cure or effective treatment despite extensive efforts. The HTT CAG repeat mutation is highly unstable both in transmissions to subsequent generations and somatically. Notably the repeat undergoes dramatic tissue-specific somatic expansion, particularly in the brain regions affected in the disorder, strongly suggesting that somatic HTT CAG length increases in target tissues contribute to HD pathogenesis. We have shown in accurate genetic HD knock-in mouse models that genes in the mismatch repair (MMR) pathway (Msh2, Msh3, Mlh1, Mlh3) are critical for CAG expansion and enhance the pathogenic process. The relevance of these findings to HD patients is indicated by a recent genome-wide association study in which MLH1 SNPs were associated with motor onset, and more generally, in which DNA repair pathways were highlighted as a source of disease modification. In this study we will: 1) perform genetic experiments in HD knock-in mice that will provide insight into mechanism(s) of MMR-dependent instability and pathogenesis; 2) test the impact of MLH1 SNPs in HD patients on gene expression, cellular phenotypes and on somatic and intergenerational repeat instability; 3) Use gene knockdown and gene editing approaches to test the impact of additional DNA repair genes, implicated as disease modifiers in patients, as modifiers of instability and striatal pathogenesis in HD knock-in mice. Together, these experiments will provide critical insight into pathways and mechanisms by which MMR/DNA repair genes modify pathogenesis, which will directly impact on the development of therapeutics that promise to target mechanism(s) that occur very early in the disease process.

描述（由申请人提供）亨廷顿氏病（HD）是由HTT基因中多态性CAG重复膨胀引起的毁灭性和致命的神经退行性疾病，它触发细胞死亡，对纹状体和皮质中神经元的特异性触发。尽管潜在的遗传突变是在20年前发现的，但仍没有治愈或有效的治疗目的地的广泛努力。 HTT CAG重复突变在传播到随后的世代和身体上都是非常不稳定的。值得注意的是，重复发生了戏剧性的组织特异性体细胞膨胀，特别是在该疾病影响的大脑区域，强烈表明，靶时间的体细胞HTT CAG长度增加会导致HD发病机理。我们已经在准确的遗传HD敲入小鼠模型中显示，这些模型中的基因不匹配修复（MMR）途径（MSH2，MSH3，MSH3，MLH1，MLH3）对于CAG扩展和增强致病过程至关重要。这些发现与HD患者的相关性通过最近全基因组关联研究表明，其中MLH1 SNP与运动发作相关，更普遍地，在该研究中，强调DNA修复途径是疾病修饰的来源。在这项研究中，我们将：1）在HD敲门小鼠中进行遗传实验，该实验将洞悉MMR依赖性不稳定性和发病机理的机制； 2）测试MLH1 SNP对HD患者的影响对基因表达，细胞表型以及躯体和代际重复不稳定性的影响； 3）使用基因敲低和基因编辑方法测试其他DNA修复基因的影响，该基因在患者中以疾病修饰的形式实现，作为HD敲入小鼠的不稳定性和纹状体发病机理的修饰剂。这些实验将共同提供对MMR/DNA修复基因修饰发病机理的途径和机制的关键见解，这将直接影响理论的发展，该理论有望靶向疾病过程中很早就发生的机制。