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Frontotemporal dementia and related disorders: transcriptomic profiling, biomarker discovery, and mechanistic insight

额颞叶痴呆及相关疾病：转录组分析、生物标志物发现和机制洞察

基本信息

批准号：
10392505
负责人：
Tania France Gendron
金额：
$ 78.09万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392505
关键词：
ALS patients Alternative Splicing Amyotrophic Lateral Sclerosis Autopsy Binding Proteins Biological Markers Blood Blood specimen Brain C-terminal C9ORF72 Candidate Disease Gene Cell Culture Techniques Cell Nucleus Cell model Cerebellum Clinical Clinical Trials Collection Complement Complex Cultured Cells Cytoplasmic Protein Data Defect Diagnosis Disease Event Exhibits Frontotemporal Dementia Frontotemporal Lobar Degenerations Future Gene Proteins Genes Genetic Transcription Genetic Translation Individual Investigation Length Measurable Medical Genetics Messenger RNA Methods Modeling Molecular Molecular Profiling Mutation Neurodegenerative Disorders Pathogenesis Pathologic Pathology Pathway interactions Patients Play Poly(A) Tail Poly(A)-Binding Proteins Preparation Prognostic Marker Property Proteins RNA RNA Processing RNA Splicing RNA-Binding Proteins Recovery Role Specimen Stress System Techniques Technology Testing Therapeutic Intervention Time Tissues Transcript Transportation Variant biomarker discovery brain tissue candidate marker causal variant cell type cohort diagnostic biomarker druggable target frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis in vivo innovation insight mRNA Stability new therapeutic target novel novel marker pharmacodynamic biomarker potential biomarker profiles in patients protein TDP-43 protein function sample collection stathmin targeted treatment transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT We seek to discover novel biomarkers and drug targets for frontotemporal dementia (FTD) and related disorders. FTD is a fatal neurodegenerative disorder that demonstrates substantial clinical, genetic, and pathological overlap with amyotrophic lateral sclerosis (ALS). Although both diseases can display TAR DNA- binding protein 43 (TDP-43) pathology, much remains unknown about the underlying mechanisms. It has been suggested that RNA processing pathways play a vital role, which is exemplified by the description of mutations in genes encoding RNA-binding proteins and the abundance of splicing defects in TDP-43 proteinopathies. Given the fact that long-read sequencing techniques have a higher accuracy in splice junctions, a better recovery of large transcripts, and detect more alternative splicing events than traditional sequencing methods that rely on short reads, we will produce full-length long-read transcriptomic data. We will examine a well- characterized pathological cohort of patients belonging to the FTD-ALS spectrum for whom frontal cortex and cerebellar tissue are available. Additionally, we will create single-nuclei long-read sequencing data, enabling us to determine in which cell type specific transcript variants are detected. This innovative approach will allow us to capture transcriptomic diversity, aiding the identification of novel, disease-specific, and/or disease-relevant transcript variants (Aim 1). We will compare the RNA signature observed in the brain to that seen in a large collection of clinical blood specimens. Moreover, we will assess differences between presymptomatic and symptomatic individuals and evaluate changes over time. These studies give us the ability to reveal interesting biomarker candidates, which will be validated in our extensive biospecimen collection (Aim 2). To elucidate the mechanisms underpinning these diseases, we will also perform in-depth mechanistic studies using various cell culture models, in vivo systems, and post-mortem tissues from patients along the FTD-ALS spectrum (Aim 3). Our original strategy, thorough characterization, and precious sample collection, will accelerate the discovery of pathological mechanisms, druggable targets and translatable biomarkers, which are highly valuable in preparation of future clinical trials for FTD and related disorders.

项目概要/摘要我们致力于发现额颞叶痴呆 (FTD) 及相关疾病的新型生物标志物和药物靶点失调。 FTD 是一种致命的神经退行性疾病，表现出大量的临床、遗传和与肌萎缩侧索硬化症（ALS）病理重叠。虽然这两种疾病都可以显示 TAR DNA- 结合蛋白 43 (TDP-43) 病理学，其潜在机制仍有很多未知之处。它一直表明 RNA 加工途径起着至关重要的作用，突变的描述就是例证编码 RNA 结合蛋白的基因和 TDP-43 蛋白病中剪接缺陷的丰度。鉴于长读长测序技术在剪接点上具有更高的准确性，更好的方法恢复大转录本，并检测比传统测序方法更多的选择性剪接事件依赖于短读，我们将产生全长长读转录组数据。我们将检查一个良好的特征为属于 FTD-ALS 谱系的患者的病理队列，这些患者的额叶皮质和小脑组织是可用的。此外，我们将创建单核长读测序数据，使我们能够以确定在哪种细胞类型中检测到特定转录物变体。这种创新方法将使我们捕获转录组多样性，帮助识别新的、疾病特异性的和/或疾病相关的转录变体（目标 1）。我们将在大脑中观察到的 RNA 特征与在大型大脑中观察到的 RNA 特征进行比较临床血液标本的采集。此外，我们将评估症状前和症状之间的差异有症状的个体并评估随时间的变化。这些研究使我们能够揭示有趣的候选生物标志物，将在我们广泛的生物样本收集中进行验证（目标 2）。为了阐明为了了解这些疾病的机制，我们还将利用各种细胞进行深入的机制研究 FTD-ALS 谱系患者的培养模型、体内系统和死后组织（目标 3）。我们独创的策略、彻底的表征和珍贵的样本收集，将加速病理机制、可药物靶点和可翻译生物标志物的发现，这些都是高度重要的对于准备 FTD 和相关疾病的未来临床试验很有价值。