Peptide and Protein Biomarkers for Amyotrophic Lateral Sclerosis (ALS)

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是最常见的成人发作的运动神经元疾病，由上下运动神经元的丧失引起，通常在症状发作后5年内致命。我们在最初资助期间的研究已经发现了ALS中的蛋白质生物标志物和ALS的候选诊断生物标志物。然而，ALS在一些患者中进展得更快（从诊断起1年内死亡），而其他患者进展得更慢（从诊断到死亡超过10年）。目前还不清楚为什么患者的进展速度差异很大，也很少有研究探讨 随着时间的推移，个体患者的疾病进展。我们建议在下一个资助期内，从ALS患者、神经系统疾病对照和健康对照中收集纵向血液和CSF样本，以产生一种新的资源。我们在收集患者和对照组的纵向样本方面有丰富的经验，并且已经有初步数据表明ALS疾病进展期间特定蛋白质水平的变化。我们将使用这些纵向样本来探索蛋白质组和细胞外RNA（exRNA），以发现ALS疾病进展的生物标志物。我们将在血液和CSF中使用靶向和无偏倚的蛋白质组学技术以及新型exRNA方法。我们假设可以鉴定出与疾病进展的临床参数（快与慢）相关的特定生物标志物特征，从而提供对调节疾病进展的分子机制的深入了解。我们提出的研究将为疾病进展期间的蛋白质组学变化提供新的见解，并表征血液和CSF中的exRNA，以发现疾病进展的新exRNA生物标志物。最后，我们将联合收割机结合这些复杂的蛋白质组和基因组数据集，以发现ALS疾病进展的生物标志物面板。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease resulting from the loss of upper and lower motor neurons, typically fatal within 5 years of symptom onset. Our studies during the initial funding period have discovered protein biomarkers in ALS and candidate diagnostic biomarkers for ALS. However ALS progresses much more rapidly in some patients (death within 1 year from diagnosis) while others progress much more slowly (greater than 10 years from diagnosis to death). It is unclear why patients progress at quite differing rates, and few studies have explored disease progression within individual patients over time. We propose in this next funding period to generate a novel resource of longitudinal blood and CSF samples collected from ALS patients, neurologic disease controls, and healthy controls. We have extensive experience in collecting longitudinal samples from patients and controls and already have preliminary data indicating specific protein levels change during ALS disease progression. We will use these longitudinal samples to explore proteomic and extracellular RNAs (exRNA) to discover biomarkers for ALS disease progression. We will use both targeted and unbiased proteomic technologies, as well as novel exRNA methodologies in both blood and CSF. We hypothesize that specific biomarker signatures can be identified that correlate to clinical parameters of disease progression (fast vs. slow), therefore providing insight into molecular mechanisms that regulate disease progression. Our proposed studies will provide novel insight into proteomic changes during disease progression and characterize exRNAs in blood and CSF to discover novel exRNA biomarkers of disease progression. Finally, we will combine these complex proteomic and genomic datasets to discover biomarker panels for ALS disease progression.