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

项目总结/摘要 我们寻求发现额颞叶痴呆（FTD）及相关疾病的新生物标志物和药物靶点。 紊乱FTD是一种致死性神经退行性疾病，在临床、遗传和免疫学方面表现出显著的 与肌萎缩侧索硬化症（ALS）的病理重叠。虽然这两种疾病都可以显示TAR DNA- 结合蛋白43（TDP-43）的病理学，许多仍然未知的潜在机制。已经 表明RNA加工途径起着至关重要的作用，这一点可以通过对突变的描述来说明。 在编码RNA结合蛋白的基因和TDP-43蛋白病中剪接缺陷的丰度。 考虑到长读段测序技术在剪接点中具有更高的准确性， 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 我们将产生全长的长读段转录组数据。我们会检查一个井- 属于FTD-ALS谱的患者的特征性病理队列， 小脑组织可用。此外，我们将创建单核长读序测序数据，使我们能够 以确定在哪些细胞类型特异性转录物变体中被检测到。这种创新的方法将使我们 捕获转录组多样性，帮助鉴定新的、疾病特异性的和/或疾病相关的 转录变体（Aim 1）。我们将比较在大脑中观察到的RNA特征和在大的 采集临床血液标本。此外，我们将评估症状前和症状后的差异。 症状个体并评估随时间的变化。这些研究让我们有能力揭示有趣的 候选生物标志物，这将在我们广泛的生物标本收集中得到验证（目标2）。阐明本 为了了解这些疾病的发病机制，我们还将使用各种细胞因子进行深入的机制研究。 培养模型、体内系统和沿着FTD-ALS谱的患者死后组织（目标3）。 我们独创的策略、彻底的表征和珍贵的样品收集，将加速 发现病理机制，可药用靶标和可翻译的生物标志物，这是高度 对准备未来FTD和相关疾病的临床试验有价值。

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.