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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.