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: 8829086
• 负责人: Clotilde Lagier-Tourenne
• 金额: $ 18.06万
• 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/8829086
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antisense Oligonucleotides; Behavioral; C9ORF72; Cessation of life; 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; Neurons; Nuclear; Pathogenesis; Patients; Phenotype; Play; Production; RNA; RNA Degradation; RNA Processing; RNA Splicing; RNA-Binding Proteins; Relative (related person); Research; Role; Safety; Seminal; Spinal Cord; TNFRSF5 gene; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Translations; Untranslated RNA; abstracting; design; gain of function; genome-wide; loss of function; mouse model; 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 人们越来越认识到 RNA 加工改变在多种疾病的发病机制中发挥着至关重要的作用。 一系列疾病，包括两种破坏性神经退行性疾病：额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症（ALS）。 2011 年六核苷酸扩增的开创性发现 C9orf72 基因作为家族性 FTD 和 ALS 最常见的原因，显着改变了我们的观点 这些神经退行性疾病。这种扩张的致病机制尚不清楚， 然而，初步观察表明要么是内源性 C9orf72 基因功能丧失，要么是 RNA毒性机制。后者最初在其他重复扩增疾病中描述，对应于 扩增的 RNA 隔离一种或多种 RNA 结合蛋白，导致广泛的错误调节 RNA 加工。在这个项目中，我们将表征小鼠模型，要么是 C9orf72 功能丧失，要么是 毒性功能获得，以揭示每种机制的相对贡献并确定动物模型 社区强烈需要解决 FTD 和 ALS 问题。在第二种方法中，我们将使用 测序的艺术方法以获得这些模型小鼠和死后的无偏差RNA谱 来自 ALS 和 FTD 患者的组织。定义一组描述疾病依赖性的 RNA 改变 分子特征是治疗策略发展的重要一步。特别是， 所提出的方法的结合将为评估安全性和 使用反义减少 C9orf72 表达的潜在治疗策略的相关性 诱导携带 C9orf72 六核苷酸扩展的 RNA 降解的寡核苷酸 (ASO)。