Core C

项目摘要/摘要：核心C C9orf72基因G4C2重复扩增是肌萎缩侧索硬化症(ALS)最常见的遗传原因 和额颞叶痴呆(FTD)，这两种毁灭性的疾病没有有效的治疗。在以下方面取得成功 开发一种治疗“c9ALS/FTD”的方法将需要更好地了解疾病的发病机制， 靶向治疗的分子通路的鉴定和生物标记物的开发 跟踪疾病进展并确认潜在治疗的目标参与。中概述的研究 项目1、2和3旨在满足这些需求，人工验证核心(核心C)将与 项目调查人员为这些重要研究提供便利。除了提供死后组织 项目1、2和3，核心C将对这些项目进行彻底的神经病理和生化分析 患者样本，包括TDP-43、P62和二肽重复(DPR)蛋白病理的定量， 小胶质细胞增多症和星形胶质细胞增多症，重复长度。核心C将类似地描述(G4C2)149中的脑组织 项目1和项目3中使用的小鼠，并测量从患者来源的神经元分化出的DPR蛋白水平 项目2中使用的诱导多能干细胞。这些数据将作为蛋白质组和 在所有三个项目中进行转录研究，以发现与疾病相关的病理机制， 以及用于临床试验的生物标记物。此外，核心C将在验证方面发挥重要作用， 蛋白水平，与ALS基因或表型相关的基因或蛋白的表达变化，以及 这可能定义了与C9ALS相关的病理生理途径。这将使用独立的 蛋白质检测和使用来自发现系列和验证系列的组织。事实上，为了确保 从C9orf72重复扩增携带者身上收集的尸检组织继续增长，Core C将发挥作用 与Core B密切合作，对参加临床研究的患者进行快速尸检并提供诊断 评估。通过这种方式，我们将进一步增加死前患者的数量 脑脊液(CSF)和死后脑组织是可用的--比较脑的重要资源 和脑脊液蛋白质组。对于后者，核心C将帮助项目3找到有前途的候选人 值得在脑脊液中进行调查的生物标记物，并帮助确定他们的顶级候选人是否可以 可作为C9ALS/FTD的脑脊液生物标志物。

PROJECT SUMMARY/ABSTRACT: CORE C G4C2 repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating diseases with no effective treatment. Success in developing a treatment for “c9ALS/FTD” will require a better understanding of disease pathomechanisms, the identification of molecular pathways amenable to therapeutic targeting, and the development of biomarkers to track disease progression and to confirm target engagement of potential therapies. The studies outlined in Projects 1, 2 and 3 aim to fill these needs, and the Human Validation Core (Core C) will work closely with Project investigators to facilitate these important studies. In addition to providing post-mortem tissues to Projects 1, 2 and 3, Core C will conduct a thorough neuropathological and biochemical analysis of these patient samples, including the quantification of TDP-43, P62 and dipeptide repeat (DPR) protein pathology, microgliosis and astrogliosis, and repeat length. Core C will similarly characterize brain tissues from (G4C2)149 mice used in Projects 1 and 3, and measure DPR protein levels in neurons differentiated from patient-derived induced pluripotent stem cells used in Project 2. These data will serve as valuable traits for the proteomic and transcriptomic studies conducted in all three projects to discover pathological mechanisms relevant to disease, and biomarkers for use in clinical trials. Furthermore, Core C will play a significant role in validating, at the protein level, expression changes of genes or proteins that associate with ALS genotypes or phenotypes, and that may define pathophysiological pathways linked to c9ALS. This will be done with independent methods of protein detection and using tissues from discovery series and validation series. Indeed, to ensure that the collection of post-mortem tissues from C9orf72 repeat expansion carriers continues to grow, Core C will work closely with Core B to obtain rapid autopsies of patients enrolled in clinical studies and provide diagnostic evaluations. In this fashion, we will further increase the number of patients from whom both antemortem cerebrospinal fluid (CSF) and postmortem brain tissue are available – important resources for comparing brain and CSF proteomes. With regards to the latter, Core C will help Project 3 home in on promising candidate biomarkers that warrant investigation in CSF, and assist in determining whether their top candidates could serve as CSF biomarkers for c9ALS/FTD.