Peptide and Protein Biomarkers for Amyotrophic Lateral Sclerosis (ALS)

描述(申请人提供)：肌萎缩侧索硬化症(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进行性丧失。它可以袭击任何年龄的成年人，尽管最常见的是50-55岁之间的人。导致这种疾病的分子机制尚不清楚，目前尚不清楚ALS的特异性生物标志物。我们使用基于蛋白质组学的质谱学的初步数据，从脑脊液(CSF)中鉴定出一组蛋白质生物标志物，在接近临床症状出现时诊断ALS具有高水平的准确性。我们建议对更大范围的肌萎缩侧索硬化症和对照受试者进行研究，以进一步验证和识别肌萎缩侧索硬化症的基于蛋白质的生物标记物。这项建议的目的是进一步探索ALS和对照受试者的脑脊液蛋白质组，以确定ALS的多肽和/或蛋白质生物标志物。我们将在一个大的无偏见的筛选中利用基于液相色谱的质谱学来区分ALS和对照对象的多肽。然后，我们将在不同的受试者组中验证我们的发现，并产生一种基于质谱学的方法，以量化脑脊液和/或血浆中区分ALS和对照受试者的特定多肽。然后，我们将使用这组生物标志物，根据发病部位、年龄、性别或疾病进展速度来区分ALS患者的亚群。这些研究将为肌萎缩侧索硬化症产生新的生物标记物，可用于未来的肌萎缩侧索硬化症诊断，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，新的研究方向和假设对于产生新的治疗靶点是必要的。我们的提案将发现ALS的新型多肽和蛋白质生物标记物。这些研究将导致对ALS的疾病机制和潜在的诊断决定因素的新见解，这些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.