C9orf72-mediated features, transcriptomic signatures, and translational studies for frontotemporal dementia and related disorders

C9orf72 介导的额颞叶痴呆和相关疾病的特征、转录组特征和转化研究

• 批准号: 10439173
• 负责人: Marka Van Blitterswijk
• 金额: $ 235.12万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439173
• 关键词: Affect; Age; Amyotrophic Lateral Sclerosis; Automobile Driving; Behavior; Bioinformatics; Biological; Biological Markers; Biometry; Brain; Brain region; C9ORF72; Candidate Disease Gene; Cell Nucleus; Cerebellum; Clinical; Collection; Complement; Complex; Data; Defect; Diagnosis; Dipeptides; Disease; Foundations; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Gene Expression; Genes; Genetic; Heterogeneity; Length; Life; Link; Measures; Mediating; Memory impairment; Methylation; Molecular; Motor Cortex; Neuraxis; Neurodegenerative Disorders; Neurosciences; Parkinsonian Disorders; Pathologic; Patients; Proteins; RNA; RNA Splicing; Repetitive Sequence; Reporting; Southern Blotting; Specimen; Spinal Cord; Symptoms; Technology; Temporal Lobe; Testing; Tissues; Transcript; Translational Research; Translations; Work; base; cell type; cohort; differential expression; disease heterogeneity; disorder control; experience; experimental study; frontal lobe; frontotemporal lobar dementia-amyotrophic lateral sclerosis; improved; innovation; innovative technologies; multidisciplinary; nervous system disorder; neuron loss; neuropathology; patient subsets; potential biomarker; psychotic symptoms; sample collection; therapeutic target; therapy development; transcriptome; transcriptome sequencing; transcriptomics; translational study

PROJECT SUMMARY/ABSTRACT We seek to perform in-depth characterization studies to unravel the clinico-pathological variability associated with frontotemporal dementia (FTD) and related neurodegenerative diseases caused by an expanded repeat in the C9orf72-SMCR8 complex subunit (C9orf72). To this end, we will examine a range of neuroanatomical regions (e.g., frontal cortex, temporal cortex, motor cortex, spinal cord, and cerebellum) and span the full spectrum from frontotemporal lobar degeneration (FTLD) – a neuropathological diagnosis of FTD – to amyotrophic lateral sclerosis (ALS). For each region, we will assess features of C9orf72-linked diseases, such as levels of C9orf72 transcripts, RNA foci, and dipeptide repeat proteins (Aim 1). Moreover, we will use an innovative targeted long-read sequencing technology to measure the size, purity, and methylation status of the expanded repeat. Additionally, we will perform whole-tissue RNA sequencing to detect overall changes in a complex context, basically taking a snapshot (Aim 2). This data will be accompanied by single-nuclei transcriptomic data to acquire gene expression levels while deciphering the cellular diversity encountered in the central nervous system. Since splicing defects have been reported in C9orf72-related diseases, we will combine short- and long-read sequencing strategies. The inclusion of long-read sequencing data creates the opportunity to obtain the full-length transcriptome with highly accurate splice junctions, even for large transcripts. These combined approaches, therefore, will enable us to capture the entire landscape of transcriptomic changes. Top hits identified through our in-depth transcriptomic studies will be further investigated in our extensive collection of clinical and pathological specimens and tested as potential biomarkers. Taken together, our detailed examinations will uncover crucial region- and disease-specific similarities and/or differences, thus laying the foundation for improved understanding of the heterogeneity associated with the FTLD-ALS spectrum and the identification of disease modifiers, translatable biomarkers, and therapeutic targets.

项目总结/摘要 我们试图进行深入的表征研究，以解开临床病理变异相关的 与额颞叶痴呆（FTD）和相关的神经退行性疾病引起的扩大重复， C9 orf 72-SMCR 8复合物亚基（C9 orf 72）。为此，我们将研究一系列神经解剖学 区域（例如，额叶皮层、颞叶皮层、运动皮层、脊髓和小脑）， 从额颞叶变性（FTLD）-FTD的神经病理学诊断-到 肌萎缩侧索硬化症（ALS）。对于每个地区，我们将评估C9 orf 72相关疾病的特征，例如 作为C9 orf 72转录物、RNA灶和二肽重复蛋白的水平（Aim 1）。此外，我们将使用 创新的靶向长读序测序技术来测量DNA的大小、纯度和甲基化状态。 扩大重复。此外，我们将进行全组织RNA测序，以检测在一个组织中的总体变化。 复杂的上下文，基本上是快照（目标2）。这些数据将伴随着单核 转录组学数据，以获得基因表达水平，同时破译细胞中遇到的多样性， 中枢神经系统由于在C9 orf 72相关疾病中已经报道了剪接缺陷，我们将 联合收割机短读和长读测序策略。包含长读段测序数据创建了 有机会获得具有高度准确的剪接点的全长转录组，即使对于大的 成绩单因此，这些综合方法将使我们能够捕捉整个景观， 转录组学变化。通过我们深入的转录组学研究确定的热门点击将进一步 在我们广泛收集的临床和病理标本中进行了研究，并进行了潜在的 生物标志物。 总之，我们的详细检查将揭示关键的区域和疾病特异性相似性 和/或差异，从而为更好地理解与 FTLD-ALS谱和疾病修饰物、可翻译的生物标志物和治疗药物的鉴定 目标的