Disease-Modifying Genes in Huntington's Diseae

亨廷顿舞蹈病的疾病修饰基因

基本信息

批准号：
9260943
负责人：
JAMES F GUSELLA
金额：
$ 61.02万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260943
关键词：
Affect Age Age of Onset Alleles Appearance Autopsy Belief Biological Biological Assay Biological Models Biological Process CAG repeat Candidate Disease Gene Cell Line Cell model Cells Cessation of life Characteristics Chorea Chromosomes, Human, Pair 15 Chromosomes, Human, Pair 4 Chromosomes, Human, Pair 8 Clinical Code Cognitive Communities DNA DNA Markers Data Data Set Development Diagnosis Diagnostic Disease European Family Foundations Gene Expression Gene Structure Generations Genes Genetic Genetic Models Genetic Variation Genome Genomic approach Genotype Goals Grant Haplotypes Heritability Home environment Human Human Genome Huntington Disease Huntington gene Impaired cognition Individual Inherited Intervention Investigation Knock-in Mouse Knowledge Length Location Maps Mathematics Modification Molecular Motor Mus Mutation Neurodegenerative Disorders Neurons Onset of illness Other Genetics Palliative Care Pathogenesis Pathway interactions Patients Persons Pharmacologic Substance Phenotype Population Positioning Attribute Process Proteins Reagent Regulation Regulatory Element Resources Route Series Societies Structure Suggestion Symptoms Testing Therapeutic Time Tissues Translations Ulysses Contracts Variant Vertebral column Work base chromosomal location clinical Diagnosis clinical development cost deep sequencing drug development drug discovery effective therapy genetic approach genetic technology genome wide association study genome-wide human disease in vivo induced pluripotent stem cell lymphoblast mind control motor disorder motor symptom mouse model mutant new technology novel positional cloning premature prevent psychiatric symptom public health relevance sample collection screening therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disorder involving motor, psychiatric and cognitive disturbances present in more than 1 in 10,000 persons but, as a family disorder with a long, costly, debilitating course, with an indirect impact on a far greater proportion of the population at great cost to the individul and society. While some palliative treatments are used, there is currently no effective treatment for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, ~15 years after diagnosis. In past decades, genetics provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. The length of the expanded HD CAG repeat is negatively correlated with the appearance of diagnostic motor signs but does not explain all of the variance in this phenotype, as other genetic factors also influence the disease process. We have used genome-wide association analysis to identify regions of the human genome which harbor disease-modifying genetic variation that acts to alter age at motor onset in human patients of European ancestry. Identification of the actual modifier genes at these locations will highlight processes occurring before clinical diagnosis to alter the course of HD and therefore to provide new, human-validated targets for traditional drug development. Our aims are to capitalize on existing genetic data and carry out focused additional genotyping of subjects to determine whether 1) these modifiers also modify cognitive and psychiatric onsets; 2) overlap with genetic factors in other disorders; and 3) show enrichment for pathways/processes that could provide targets for intervention. These findings, combined in each associated region with dense haplotyping, sequencing and expression analysis of the loci involved and testing of candidate genes in established disease-relevant assays in human induced pluripotent stem cells and precise genetic HD mouse models will converge to identification of the gene responsible for disease modification and its functional variation. The product of this work will be a knowledge of specific genes and pathways that can delay HD pathogenesis in human patients, of the degree to which they broadly affect both HD motor and other phenotypes and of the potential mechanisms by which they act. We will also provide critical cellular and mouse model resources necessary to rapidly drive the findings toward translation for the HD community. It is our belief that the identification of novel targets, implicated by the natural variation in biological processes ongoing in HD patients themselves, will provide a firm foundation for developing effective pharmaceutical interventions to push those processes toward a strong therapeutic benefit in HD patients. Thus, the promise of this grant is a new and powerful route to fulfilling the greatest need of HD patients and families: an effective treatment to delay of prevent onset of the disease.

描述（由申请人提供）：亨廷顿病 (HD) 是一种破坏性的神经退行性疾病，涉及运动、精神和认知障碍，每 10,000 人中就有 1 人存在这种疾病，但作为一种家庭疾病，其病程漫长、昂贵、使人衰弱，会间接影响患者的健康。尽管使用了一些姑息治疗，但目前尚无有效的治疗方法来预防该疾病的临床发作或延迟其发生。诊断后约 15 年，不可避免地走向过早死亡在过去的几十年里，遗传学提供了将 HD 基因定位到 4 号染色体的工具，并最终将其突变识别为大蛋白质编码序列中扩展的 CAG 三核苷酸重复。扩展的 HD CAG 重复序列的长度与诊断运动体征的出现呈负相关，但不能解释该表型的所有差异，因为其他遗传因素也影响疾病过程。识别人类基因组中隐藏的区域疾病修饰遗传变异可以改变欧洲血统的人类患者运动开始时的年龄，鉴定这些位置发生的实际修饰基因将突出临床诊断之前改变 HD 病程的过程，从而提供新的、人类的治疗方法。我们的目标是利用现有的遗传数据，对受试者进行有针对性的额外基因分型，以确定 1) 这些修饰因素是否也能改变认知和精神疾病的发病；2) 与其他疾病的遗传因素重叠； 3) 丰富的途径/过程可以提供干细胞和精确的遗传HD小鼠模型，该模型将集中于识别负责疾病修饰及其功能变异的基因。这项工作的成果将是对特定疾病的了解。可以延迟人类 HD 发病机制的基因和途径，其程度我们还将提供必要的关键细胞和小鼠模型资源，以快速推动HD社区的研究成果转化。的新目标， HD 患者本身发生的生物过程的自然变异所涉及的，将为开发有效的药物干预措施提供坚实的基础，以推动这些过程对 HD 患者产生强大的治疗益处。因此，这项资助的承诺是一条新的、强大的途径。满足HD患者及其家属的最大需求：有效治疗延缓或预防疾病的发生。