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

项目摘要/摘要 我们寻求发现额颞部痴呆(FTD)及其相关的新生物标记物和药物靶点 精神错乱。FTD是一种致命的神经退行性疾病，表现出显著的临床、遗传和 病理上与肌萎缩侧索硬化症(ALS)重叠。尽管这两种疾病都可以显示TAR DNA- 结合蛋白43(TDP-43)的病理机制尚不清楚。一直以来 认为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。 鉴于长读测序技术在剪接连接中具有更高的准确性，更好的 回收大转录本，并检测比传统测序方法更多的选择性剪接事件 依赖于短阅读，我们将产生全长的长阅读转录数据。我们将检查一口井- 属于FTD-ALS谱的患者的特征性病理队列，对于这些患者，额叶皮质和 小脑组织可用。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本变体。这种创新的方法将使我们能够 捕获转录多样性，帮助识别新的、特定于疾病的和/或与疾病相关的 文字记录变体(目标1)。我们将比较在大脑中观察到的RNA签名与在 采集临床血液标本。此外，我们将评估症状前和症状前的差异 对有症状的个体进行评估，并评估随时间的变化。这些研究让我们有能力揭示有趣的 候选生物标记物，这将在我们广泛的生物样品收集中得到验证(目标2)。为了澄清 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谱的培养模型、体内系统和患者的死后组织(目标3)。 我们独创的策略、彻底的人物塑造和宝贵的样本收集将加速 病理机制、可用药靶点和可翻译生物标志物的发现，这些都是 对未来FTD和相关疾病的临床试验的准备工作有重要价值。

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.