Genetic Studies of Huntington's Disease

亨廷顿病的遗传学研究

• 批准号: 7883255
• 负责人: RICHARD H MYERS
• 金额: $ 26.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7883255
• 关键词: 2q33; 4p16; 6p22.3; Accounting; Activities of Daily Living; Adult; Affect; Age; Age of Onset; Animal Model; Animals; Bioinformatics; Biological; Boston; CAG repeat; Candidate Disease Gene; Chromosomes; Clinic; Clinical; Clinical Data; Collaborations; Collection; Consent; Data; Delusions; Disease; Exons; Family; Feeling suicidal; Follow-Up Studies; Gene-Modified; Genes; Genetic; Genetic Epistasis; Genome; Genome Scan; Genotype; Haplotypes; Heritability; Human; Huntington Disease; Individual; Institutes; Intervention; Length; Link; Linkage Disequilibrium Mapping; Literature; Lod Score; Maps; Measures; Microsatellite Repeats; Modeling; Motor; Mus; Neurologic Examination; Onset of illness; Parents; Participant; Patients; Pattern; Persons; Principal Investigator; Process; Proteins; Protocols documentation; Publishing; RNA Interference; Recruitment Activity; Research; Resources; Sampling; Siblings; Single Nucleotide Polymorphism; Source; System; Testing; Therapeutic Agents; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Trinucleotide Repeat Expansion; Universities; Variant; Visit; Zebrafish; base; cohort; density; fly; gene interaction; genetic linkage analysis; genetic pedigree; human Huntingtin protein; human disease; insight; motor impairment; mouse model; programs; research study; sex; trait

Project 2 Genetic Studies of Huntington's Disease Since the discovery of the Huntington's disease (HD) gene in February of 1993, much of the research focus into the cause and treatment has relied on transgenic mouse models, containing either full length or shorter first exon bearing expanded trinucleotide repeats. These studies have been remarkable in their capacity to lend insight into the processes leading to huntingtin (htt) aggregation, now recognized as a critical hallmark of the disease. Further, the use of transgenic mice has yielded promising leads for therapeutic intervention as different treatments are found to delay onset and slow progression in these mice. Presently, much HD research focuses on mouse and other transgenics (e.g. fly, zebrafish, etc.). Yet, the genetic mechanisms regulating the human disease may differ markedly from those seen in animal models, and there is critical need to maintain human research component in the multi-pronged attack on the disease. We propose a coordinated effort among Projects 1, 2, and 3 of the HD Center to identify the genetic modifiers regulating HD onset age in a cohort of 352 pedigrees containing 754 sibling pairs. A unique set of 282 HD cases with unusually young or old onset ages, given their repeat sizes, will be used to validate finding of association in the families. The highlight of our proposal is the pursuit of a genetic modifier at 6q23- 24, identified by linkage analysis in two independent samples, HD MAPS I [LOD=3.8] and HD MAPS II [LOD=2.8] with a combined LOD score of 5.1.This compelling finding will be investigated through genotyping 1536 SNPs, in 1200 persons, in collaboration with the Broad Institute. Further, we will investigate four other regions with varying support for linkage 4p16 [LOD=1.92], 18q22 [LOD=1.83], 6p22.3 [LOD=1.41], and 2q33 [LOD=1.54]. We will explore carefully selected candidate genes and huntingtin interacting proteins under these peaks and in other regions of the genome. In a newly crafted AIM 2, we will explore gene-gene interaction models as well as two-locus linkage analysis. We present new preliminary data for a revised AIM 3, showing the first ever studies of heritability for other important HD clinical features, including motor impairment and psychiatric features. We will conduct linkage analysis and candidate gene studies for these traits. The identification of genetic modifiers in HD holds promise for the recognition of substances which may be invoked for pharmacologic intervention in this devastating disease.

项目2亨廷顿氏病的遗传学研究 自从1993年2月发现了亨廷顿病（HD）基因以来， 对病因和治疗的关注依赖于转基因小鼠模型，其含有全长或 带有扩展的三核苷酸重复序列的较短的第一外显子。这些研究在其 能够深入了解导致亨廷顿蛋白（htt）聚集的过程，现在被认为是一种 这种疾病的关键特征此外，使用转基因小鼠已经产生了有希望的线索， 发现治疗干预作为不同的治疗在这些小鼠中延迟发作和减缓进展。 目前，许多HD研究集中在小鼠和其他转基因动物（例如苍蝇，斑马鱼等）。然而 调节人类疾病的遗传机制可能与动物模型中所见的明显不同， 在多管齐下防治艾滋病的工作中，迫切需要保持对人类的研究。 我们建议在HD中心的项目1、2和3之间进行协调努力，以确定遗传 在包含754对兄弟姐妹的352个家系队列中调节HD发病年龄的调节剂。一套独特的 282例发病年龄异常年轻或年老的HD病例，考虑到其重复样本量，将用于验证 在家庭中发现关联。我们计划的重点是在6 q23寻找一个基因修饰者- 24个，通过两个独立样品（HD MAPS I [LOD=3.8]和HD MAPS II）中的连锁分析鉴定 [LOD=2.8]，合并LOD评分为5.1。将通过以下方法研究这一令人信服的发现： 与布罗德研究所合作，对1200人中的1536个SNP进行基因分型。此外，我们将 研究其他四个不同支持连锁的区域4p 16 [LOD=1.92]，18 q22 [LOD=1.83]，6p22.3 [LOD=1.41]和2 q33 [LOD=1.54]。我们将探索精心挑选的候选基因和亨廷顿 在这些峰下和基因组的其他区域中的相互作用蛋白质。在新制作的AIM 2中，我们将 探索基因-基因相互作用模型以及双位点连锁分析。我们提出了新的初步 修订版AIM 3的数据，显示了其他重要HD临床特征遗传性的首次研究， 包括运动障碍和精神特征。我们将进行连锁分析和候选基因 研究这些特征。HD中遗传修饰剂的鉴定有望识别 这些物质可能被用于对这种毁灭性疾病进行药物干预。