Project 2: Disease Mechanisms in Frontotemporal Dementia Linked to C9orf72 Expans

项目 2：与 C9orf72 相关的额颞叶痴呆疾病机制扩展

• 批准号: 9256413
• 负责人: Clotilde Lagier-Tourenne
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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/9256413
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antisense Oligonucleotides; Autopsy; Behavioral; C9ORF72; Communities; Disease; Frontotemporal Dementia; Genes; Genetic; Genetic Transcription; High-Throughput Nucleotide Sequencing; Link; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Profiling; Motor Neuron Disease; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Play; Production; RNA; RNA Degradation; RNA Processing; RNA Splicing; RNA-Binding Proteins; Research; Role; Safety; Seminal; Spinal Cord; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Translations; Untranslated RNA; design; gain of function; genome-wide; loss of function; mouse model; neuron loss; overexpression; polypeptide; therapeutic development; tool

PROJECT 2 LAGIER TOURENNE ABSTRACT RNA processing alterations are increasingly recognized to play a crucial role in the pathogenesis of a wide range of diseases including two devastating neurodegenerative conditions, frontal temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The seminal discovery in 2011 of a hexanucleotide expansion in the C9orf72 gene as the most common cause of familial FTD and ALS significantly changed our perspective of these neurodegenerative diseases. The pathogenic mechanisms of this expansion are not understood, however, with initial observations pointing to either a loss of function of the endogenous C9orf72 gene or an RNA toxicity mechanism. The later, initially described in other repeat-expansion diseases, corresponds to the sequestration of one or more RNA binding protein(s) by expanded RNAs leading to broad misregulation of RNA processing. In this project, we will characterize mice modeling either a loss of C9orf72 function or a toxic gain of function to unravel the relative contributions of each mechanism and identify animal models strongly needed by the community to tackle FTD and ALS. In a second approach, we will use state of the art methods in sequencing to obtain an unbiased RNA profile in these model mice and in post-mortem tissues from ALS and FTD patients. Defining a set of RNA alterations that delineate a disease-dependent molecular signature is an important step toward the development of therapeutic strategies. In particular, the combination of the proposed approaches will provide crucial information to evaluate the safety and pertinence of a potential therapeutic strategy to reduce C9orf72 expression using antisense oligonucleotides (ASOs) that induce degradation of RNAs carrying the C9orf72 hexanucleotide expansion.

项目2 Lagier Tourenne摘要 RNA处理的改变越来越被认识到在广泛的发病机理中起着至关重要的作用 疾病范围包括两个毁灭性神经退行性疾病，额叶痴呆症（FTD） 和肌萎缩性侧索硬化症（ALS）。 2011年的六核苷酸扩展的开创性发现 C9ORF72基因是家族性FTD和ALS的最常见原因，并显着改变了我们的观点 这些神经退行性疾病。这种扩展的致病机制尚不清楚， 但是，最初的观察表明内源性C9orf72基因的功能丧失或 RNA毒性机制。后来的，最初在其他重复膨胀疾病中描述的，对应于 通过膨胀的RNA隔离一个或多个RNA结合蛋白，导致广泛的不正直 RNA处理。在这个项目中，我们将表征对C9orf72功能损失或A 功能的有毒物质增益以揭示每种机制的相对贡献并识别动物模型 社区强烈需要解决FTD和ALS。在第二种方法中，我们将使用 测序中的ART方法以在这些模型小鼠和验尸中获得无偏的RNA曲线 来自ALS和FTD患者的组织。定义一组RNA改变，这些改变描述了疾病依赖性的 分子签名是朝着治疗策略发展的重要一步。特别是 拟议方法的组合将提供关键信息以评估安全性和 使用反义降低C9ORF72表达的潜在治疗策略的相关性 寡核苷酸（ASO）诱导携带C9ORF72六核苷酸膨胀的RNA降解。