Project 3

项目总结/摘要：项目3 在肌萎缩侧索硬化症（ALS）中识别疾病机制的一个主要障碍是肌萎缩侧索硬化症的异质性。 疾病的性质。ALS患者表现出各种各样的临床表现，进展速度和 潜在的遗传风险因素。ALS更可能是一种综合征，而不是一种单一的疾病， 我们称之为肌萎缩侧索硬化症。我们解开ALS病理生理学的方法是 重点关注特定的遗传定义人群，其中疾病由共同的基础疾病定义。 机制在这里，携带C9 orf 72 G4 C2六核苷酸重复扩增突变（c9 ALS）的人是 基因定义的人口。与散发性ALS（sALS）相反，在散发性ALS中， 环境和未知因素驱动疾病，一种常见的致病病理生理学基础 c9ALS。这个命题是，调查这个相对同质的ALS遗传亚群将提供一个 了解疾病机制和开发治疗方法的机会之窗。希望在于 在这一较小患者群体中的发现将适用于较大的ALS群体。本课题 将使用下一代质谱和系统生物学分析来发现疾病的生物标志物 路径和进展。在具体目标1中，我们将询问来自c9 ALS和sALS的人类运动皮层 患者生成定义c9 ALS的蛋白质组学网络和模块。在具体目标2中，我们将合作伙伴 与项目1的研究人员一起定义C9 orf 72 G4 C2小鼠模型中的蛋白质组网络;这将允许 我们分析了疾病进展过程中几个时间点大脑中蛋白质组的变化。此外，本发明还提供了一种方法， 用靶向G4 C2的反义寡核苷酸（阿索）处理的小鼠脑的蛋白质组学分析 转录物将允许鉴定与疾病修饰药物相关的蛋白质标记。在 具体目标3，人类和小鼠疾病共同的蛋白质组特征将在CSF中靶向 来自c9 ALS患者和无症状C9 orf 72扩增携带者的样本， 纵向分析。该项目的最终目标是发现新的疾病生物标志物 这对于正在进行的疾病发病机制研究以及 未来的临床试验

PROJECT SUMMARY/ABSTRACT: PROJECT 3 A major hurdle to identifying disease mechanisms in amyotrophic lateral sclerosis (ALS) is the heterogeneous nature of the disease. People with ALS exhibit a wide variety of clinical presentations, rates of progression and underlying genetic risk factors. ALS is more likely a syndrome rather than a single disease that leads to a recognizable clinical phenotype that we call ALS. Our approach to unraveling the pathophysiology of ALS is to focus on a specific genetically-defined population where the disease is defined by a common underlying mechanism. Here, people carrying the C9orf72 G4C2 hexanucleotide repeat expansion mutation (c9ALS) are the genetically defined population. As opposed to sporadic ALS (sALS), where an array of genetic, environmental, and unknown factors drive disease, a common disease-causing pathophysiology underlies c9ALS. The proposition is that investigating this relatively homogenous ALS genetic subgroup will provide a window of opportunity for understanding disease mechanisms and developing treatments. The hope is that discoveries in this smaller group of patients will be applicable to the larger ALS population. In this project, we will use next generation mass spectroscopy and systems biology analysis to discover biomarkers of disease pathways and progression. In Specific Aim 1, we will interrogate human motor cortex from c9ALS and sALS patients to generate proteomic networks and modules that define c9ALS. In Specific Aim 2, we will partner with the investigators of Project 1 to define proteomic networks in a C9orf72 G4C2 mouse model; this will allow us to analyze proteomic changes in brain at several time points during disease progression. In addition, proteomic analysis of brains from mice treated with an antisense oligonucleotide (ASO) targeting G4C2 transcripts will allow for the identification of protein signatures associated with a disease-modifying drug. In Specific Aim 3, proteomic signatures common to both human and mouse disease will be targeted in CSF samples from c9ALS patients and asymptomatic C9orf72 expansion carriers, both in cross sectional and longitudinal analyses. The ultimate goal of this project is the discovery of novel biomarkers of disease pathways and progression that will be important for ongoing research into disease pathogenesis and also for future clinical trials.