Core C

项目总结/摘要：核心C C9 orf 72中的G4 C2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方法。成功 开发“c9 ALS/FTD”的治疗需要更好地理解疾病的病理机制， 鉴定适合治疗靶向的分子途径，并开发生物标志物， 跟踪疾病进展，并确认潜在治疗的目标参与。概述的研究 项目1、2和3旨在满足这些需求，人类验证核心（Core C）将与 项目研究人员，以促进这些重要的研究。除了提供死后组织给 项目1、2和3，核心C将对这些患者进行彻底的神经病理学和生化分析。 患者样本，包括TDP-43、P62和二肽重复序列（DPR）蛋白病理学的定量， 小胶质细胞增生和星形胶质细胞增生以及重复长度。核心C将类似地表征（G4 C2）149的脑组织 在项目1和3中使用的小鼠，并测量从患者来源的分化的神经元中的DPR蛋白水平。 在项目2中使用的诱导多能干细胞。这些数据将作为蛋白质组学的有价值的特征， 在所有三个项目中进行转录组学研究，以发现与疾病相关的病理机制， 和用于临床试验的生物标志物。此外，核心C将在验证中发挥重要作用， 蛋白质水平，与ALS基因型或表型相关的基因或蛋白质的表达变化，以及 可能定义与c9 ALS相关的病理生理学途径。这将通过独立的方法来完成， 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C9 orf 72重复扩增载体收集的死后组织继续增长，核心C将发挥作用 与核心B密切合作，对临床研究中入组的患者进行快速尸检， 评价。通过这种方式，我们将进一步增加病人的数量， 脑脊液（CSF）和死后脑组织是可用的-重要的资源，比较大脑 和CSF蛋白质组。关于后者，核心C将帮助项目3找到有前途的候选人 生物标志物，保证在CSF中的调查，并协助确定他们的最佳候选人是否可以 作为c9 ALS/FTD的CSF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.