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Investigating disease Mechanisms in C9orf72-linked ALS/FTD

研究 C9orf72 相关 ALS/FTD 的疾病机制

基本信息

批准号：
9066822
负责人：
Jiou Wang
金额：
$ 35.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2015-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066822
关键词：
Address Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Autophagocytosis Base Sequence Binding Biochemical Brain C9ORF72 Cells Clinical Coupling DNA Defect Dementia Diagnosis Disease Elements Epigenetic Process Etiology Foundations Frontotemporal Dementia G-Quartets Gene Expression Genes Genetic Genetic Transcription Genetic study Genome Goals Health Hereditary Disease Human Human Genome Huntington Disease Hybrids In Vitro Indium Intervention Investigation Knockout Mice Knowledge Lead Length Link Mediating Microsatellite Repeats Modeling Molecular Molecular Conformation Molecular Genetics Motor Cortex Motor Neurons Nerve Degeneration Neurodegenerative Disorders Neurologic Neuromuscular Diseases Nucleic Acid Conformation Nucleic Acids Nucleolar Proteins Nucleotides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Plant Roots Proteins Public Health RNA RNA-Binding Proteins Regulation Research Role Short Tandem Repeat Societies Stress Structure Temporal Lobe Therapeutic Tissues Toxic effect Translations Work effective therapy frontal lobe gene function genetic approach in vivo induced pluripotent stem cell infancy insight loss of function molecular pathology mouse model nervous system disorder neurotoxicity novel strategies novel therapeutic intervention nucleic acid structure nucleolin patient subsets therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Nucleotide repeat elements, including microsatellites or short tandem repeats, are common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to nearly 40 different types of genetic disorders, primarily neurological and neuromuscular disorders. Our understanding of how these repeat elements in the human genome cause diseases is still at its infancy. Recently, a hexanucleotide repeat expansion in a noncoding region of C9orf72 was linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 repeat expansion represents the most common genetic cause of both familial and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the brain and is the second most common type of dementia for people older than 65; the C9orf72 repeat expansion is also one of the most common genetic causes for FTD. The C9orf72 repeat expansion is also found to contribute to Alzheimer's disease and Huntington's disease. To help relieve the public health burden associated with these diseases, it is important to understand the mechanisms underlying the pathogenesis. We have recently discovered that the C9orf72 nucleotide repeat structures initiate molecular cascades of disease. The goal of the proposed project is to elucidate the mechanisms through which nucleotide repeat expansions, such as that in C9orf72, lead to molecular defects and neuronal toxicity. The specific aims are to identify and characterize key biochemical features of the repeat expansion, to delineate the pathways through which the pathogenesis is generated, and to identify potential intervention strategies. The proposed studies, which combine biochemical, molecular, and genetic approaches, are expected to provide insight into fundamental mechanisms of neurodegeneration associated with nucleotide repeats that may ultimately leads to novel approaches for treating relevant neurodegenerative diseases.

描述(申请人提供)：核苷酸重复元件，包括微卫星或短串联重复，在真核基因组中很常见。短核苷酸重复序列的扩展与近40种不同类型的遗传疾病有关，主要是神经和神经肌肉疾病。我们对人类基因组中这些重复元件如何导致疾病的理解仍处于初级阶段。最近，C9orf72非编码区的六核苷酸重复序列的扩张与神经退行性疾病肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)有关。ALS以运动神经元丧失为特征，C9orf72重复扩增是家族性和散发性ALS最常见的遗传原因。FTD的特点是大脑的额叶和颞叶退化，是65岁以上人群中第二常见的痴呆类型；C9orf72重复扩增也是FTD最常见的遗传原因之一。C9orf72重复扩增也被发现与阿尔茨海默病和亨廷顿病有关。为了帮助减轻与这些疾病相关的公共卫生负担，重要的是了解其发病机制。我们最近发现，C9orf72核苷酸重复结构启动了疾病的分子级联反应。该项目的目标是阐明核苷酸重复扩张(如C9orf72中的核苷酸重复扩张)导致分子缺陷和神经元毒性的机制。其具体目的是确定和表征重复扩大的关键生化特征，描绘发病机制的发生途径，并确定潜在的干预策略。这些拟议的研究结合了生化、分子和遗传学的方法，有望深入了解与核苷酸重复相关的神经退行性变的基本机制，最终可能导致治疗相关神经退行性疾病的新方法。