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）是最常见的运动神经元退行性疾病，其特征是脊髓、脑干和大脑皮层运动神经元的进行性丧失。它可以侵袭任何年龄的成年人，但最常见于50-55岁之间。导致这种疾病的分子机制尚不清楚，ALS特异性的生物标志物目前尚不清楚。我们使用基于质谱的蛋白质组学的初步数据从脑脊液（CSF）中鉴定出一组蛋白质生物标志物，在临床症状发作时诊断ALS具有高水平的准确性。我们建议对更大的ALS群体和对照受试者进行研究，以进一步验证和鉴定基于蛋白质的ALS生物标志物。本研究的目标是进一步探索ALS和对照受试者的脑脊液蛋白质组，以鉴定ALS的肽和/或蛋白质生物标志物。我们将利用液相色谱质谱法在一个大的无偏筛选肽区分ALS与对照受试者。然后，我们将在不同的受试者组中验证我们的发现，并生成一种基于质谱的方法来量化脑脊液和/或血浆中区分ALS与对照受试者的特定肽。然后，我们将使用这组生物标志物根据疾病发病部位、年龄、性别或疾病进展速度来区分ALS患者的亚群。这些研究将产生新的ALS生物标志物，可用于未来的ALS诊断，并在临床试验中测试其监测疾病进展或药物疗效的能力。公共卫生相关性：肌萎缩侧索硬化症（ALS）的分子机制尚不清楚，需要新的研究方向和假设来产生新的治疗靶点。我们的建议将发现新的肽和蛋白质生物标志物的ALS。这些研究将导致对ALS的疾病机制和潜在诊断决定因素的新见解，可以在未来的研究中进一步探索。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron degenerative disease and is characterized by a progressive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. It can strike adults of any age, though is most common between the ages of 50-55 years. The molecular mechanisms that cause this disease are unclear and biomarkers specific for ALS are currently unknown. Our preliminary data using mass spectrometry based proteomics identified a panel of protein biomarkers from cerebrospinal fluid (CSF) with a high level of accuracy for diagnosing ALS near the time of clinical symptom onset. We propose to examine a much larger group of ALS and control subjects to further validate and identify protein based biomarkers for ALS. The goals of this proposal are to further explore the CSF proteome of ALS and control subjects to identify peptide and/or protein biomarkers for ALS. We will utilize liquid chromatography based mass spectrometry in a large unbiased screen for peptides that distinguish ALS from control subjects. We will then validate our findings in separate subject groups and generate a mass spectrometry based method to quantify specific peptides within the CSF and/or plasma that distinguish ALS from control subjects. We will then use this panel of biomarkers to distinguish sub-populations of ALS patients based on site of disease onset, age, gender, or rate of disease progression. These studies will generate novel biomarkers for ALS that could be used in future diagnostics for ALS and tested for their ability to monitor disease progression or drug efficacy in clinical trials. PUBLIC HEALTH RELEVANCE: The molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are unclear and new research directions and hypotheses are necessary to generate novel therapeutic targets. Our proposal will uncover novel peptide and protein biomarkers for ALS. These studies will lead to new insights into disease mechanisms and potential diagnostic determinants for ALS that can be further explored in future studies.