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：
10180652
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/10180652
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.

项目摘要/摘要我们试图发现额颞痴呆（FTD）和相关的新型生物标志物和药物靶标疾病。 FTD是一种致命的神经退行性疾病，表现出大量的临床，遗传和与肌萎缩性侧索硬化症（ALS）的病理重叠。尽管两种疾病都可以显示焦油DNA- 结合蛋白43（TDP-43）病理学，关于潜在机制仍然未知。它一直提出RNA处理途径起着至关重要的作用，这是突变描述的例证在编码RNA结合蛋白的基因和TDP-43蛋白质病中的剪接缺陷中。鉴于长阅读测序技术在接头连接方面具有更高的精度，所以比传统测序方法恢复大型笔录并检测更多的替代剪接事件依靠简短的读取，我们将产生全长的长读转录组数据。我们将检查一个很好的表征了属于FTD-ALS谱系的患者的病理群体，额叶皮质和可以使用小脑组织。此外，我们将创建单核长读测序数据，使我们能够确定检测到哪种细胞类型的特定成绩单变体。这种创新的方法将使我们捕获转录组的多样性，帮助鉴定新型，疾病特异性和/或与疾病相关的鉴定成绩单变体（AIM 1）。我们将比较大脑中观察到的RNA特征与在大的收集临床血液标本。此外，我们将评估预症状和有症状的人并评估随着时间的变化。这些研究使我们能够揭示有趣的生物标志物候选人，将在我们广泛的生物环境收藏中进行验证（AIM 2）。阐明支撑这些疾病的机制，我们还将使用各种细胞进行深入的机械研究培养模型，体内系统和沿FTD-ALS频谱患者的验尸组织（AIM 3）。我们最初的策略，彻底的特征和宝贵的样本收集，将加速发现病理机制，可药物靶标和可翻译生物标志物的发现，这是高度的在准备FTD和相关疾病的未来临床试验方面很有价值。