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：
9463801
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/9463801
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 Huntington protein 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（申请人证明）：亨廷顿氏病（HD）是一种毁灭性的神经培养性疾病，涉及超过10,000人的运动障碍，但作为一种长期，昂贵，昂贵的家庭障碍，对远距离的影响有间接影响对个人和社会的更大建议无效，对于疾病的疾病发作或诊断后的15年后，遗传学的遗传学是遗传学，最终识别出4年的遗传学，并最终在大型蛋白质的编码序列中，Mutatatin的CAG trin核苷酸重复序列（称为Huntingtin）影响疾病的过程。突出显示在临床诊断之前发生的过程，以改变HD的进程，因此为传统的药物药物开发提供了新的，人类验证的靶标，以确定1）这些修饰符是否也在可以进行干预的途径。这项工作的乘积将是对人类患者的HD发病机理的知识，而Broady HD运动和其他表型的程度以及它们OCT AR和小鼠模型的潜在机制。迅速推动识别新目标的发现所需的资源。 HD患者本身的自然过程含义，我的药物干预措施将过程推向了HD患者的强大治疗益处，因此，满足了HD患者和家庭的最大需求：有效的治疗方法：延迟疾病。