Project 3

项目摘要/摘要：项目3 肌萎缩侧索硬化症(ALS)发病机制的一个主要障碍是异质性 疾病的性质。肌萎缩侧索硬化症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更有可能是一种综合征，而不是一种导致 可识别的临床表型，我们称之为肌萎缩侧索硬化症。我们解开肌萎缩侧索硬化症的病理生理学的方法是 关注特定的基因定义的人群，其中疾病是由共同的潜在疾病定义的 机制。在这里，携带C9orf72 G4C2六核苷酸重复序列扩展突变(C9ALS)的人是 基因定义的种群。与散发性肌萎缩侧索硬化症(SAL)相反，在SAL中， 环境和未知因素导致疾病，这是一种常见的致病病理生理学基础 C9ALS。这个命题是，研究这个相对同质的ALS基因亚群将提供一种 这是了解疾病机制和开发治疗方法的机会之窗。希望是这样的 在这一较小患者群体中的发现将适用于更大的ALS人群。在这个项目中，我们 将使用下一代质谱学和系统生物学分析来发现疾病的生物标志物 路径和进程。在特定的目标1中，我们将询问来自c9als和sals的人类运动皮质。 患者生成定义c9ALS的蛋白质组网络和模块。在具体目标2中，我们将合作 与项目1的研究人员一起在C9orf72 G4C2小鼠模型中定义蛋白质组网络；这将允许 美国将分析疾病进展过程中几个时间点的大脑蛋白质组变化。此外, G4C2反义寡核苷酸处理小鼠脑的蛋白质组学分析 转录本将允许识别与疾病修改药物相关的蛋白质签名。在……里面 具体目标3，人类和小鼠疾病共同的蛋白质组特征将成为脑脊液的靶标 取自C9ALS患者和无症状C9orf72扩张型携带者的横断面和 纵向分析。这个项目的最终目标是发现新的疾病生物标记物。 途径和进展对于正在进行的疾病发病机制的研究以及对 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.