Project 1

项目1

基本信息

批准号：
10415047
负责人：
John David Fryer
金额：
$ 38.91万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415047
关键词：
Address Affect Amyotrophic Lateral Sclerosis Antisense Oligonucleotides Autopsy Behavior Behavioral Brain Brain region C9ORF72 Cell Nucleus Cells Clinic Collaborations Collection Data Dipeptides Disease Disease Pathway Gene Expression Profile Genes Genetic Genetic Transcription Human In Situ Hybridization Individual Mediating Modeling Molecular Motor Cortex Mouse Protein Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Nuclear RNA Outcome Measure Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peptides Prevention trial Proteins Proteomics RNA RNA metabolism RNA-Binding Proteins Research Design Sampling Shapes Signal Transduction Spinal Cord Testing Tissues Toxic effect Transcript Translations brain tissue c9FTD/ALS cell type cohort experimental study frontotemporal lobar dementia-amyotrophic lateral sclerosis gain of function human tissue mouse model neuroinflammation neuropathology novel programs response sporadic amyotrophic lateral sclerosis targeted treatment therapeutic target transcriptome sequencing treatment group treatment trial

项目摘要

PROJECT SUMMARY/ABSTRACT: PROJECT 1 A hexanucleotide (G4C2) repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively referred to as c9ALS/FTD. Mounting evidence indicates repeat-containing transcripts cause c9ALS/FTD through gain-of-function mechanisms by producing toxic RNA foci and dipeptide repeat (DPR) proteins. Our central hypothesis in this proposal is that each of these pathologies (RNA foci, DPR proteins) elicits both common and cell-specific molecular cascades. To address this question, we will perform bulk and single-nucleus RNAseq (sn-RNAseq) using our novel c9ALS/FTD mouse model and patient tissues to uncover the whole and single-cell landscape of transcriptional changes that occur during c9ALS pathogenesis. Our single-nucleus approach will also allow us to test how an individual neuron with RNA foci and/or DPR protein pathology is different than even a neighboring neuron without apparent pathology. Moreover, we will treat our c9ALS/FTD mouse model with antisense oligonucleotides (ASO) targeting repeat-containing transcripts, which has been shown to reduce RNA foci burden, DPR protein pathology and other anomalies in various c9ALS models. Treatment will be initiated at early and late stages of disease to determine the optimal timing of ASO treatment for mitigating neuropathology, behavioral deficits, and the single-cell landscape of transcriptional changes. Our studies will identify and validate high value therapeutic targets to treat c9ALS/FTD.

项目摘要/摘要：项目 1 C9orf72 基因中的六核苷酸 (G4C2) 重复扩增是最常见的遗传原因肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD)，统称为 c9ALS/FTD。越来越多的证据表明，包含重复的转录本通过功能获得导致 c9ALS/FTD 通过产生有毒 RNA 焦点和二肽重复 (DPR) 蛋白的机制。我们的中心假设是建议是，这些病理学（RNA 病灶、DPR 蛋白）中的每一种都会引起常见的和细胞特异性的分子级联。为了解决这个问题，我们将进行批量和单核 RNAseq (sn-RNAseq) 使用我们的新型 c9ALS/FTD 小鼠模型和患者组织来揭示整个和单细胞景观 c9ALS 发病机制中发生的转录变化。我们的单核方法也将允许我们来测试具有 RNA 焦点和/或 DPR 蛋白病理学的单个神经元与单个神经元有何不同邻近的神经元没有明显的病理变化。此外，我们将用以下方法治疗我们的 c9ALS/FTD 小鼠模型：反义寡核苷酸（ASO）靶向包含重复的转录本，已被证明可以减少各种 c9ALS 模型中的 RNA 病灶负荷、DPR 蛋白病理学和其他异常。治疗将是在疾病的早期和晚期阶段启动，以确定 ASO 治疗缓解的最佳时机神经病理学、行为缺陷和转录变化的单细胞景观。我们的研究将识别并验证治疗 c9ALS/FTD 的高价值治疗靶点。