Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

描述（申请人提供）：阿尔茨海默病（AD）的早期和准确诊断迫切需要生物标志物。SurroMed正在使用高通量、多重蛋白质组学方法检测、鉴定和定量动物模型和人类脑脊液（CSF）标本中的大量推定生物标志物。目的建立一种利用液相色谱-质谱联用技术对脑脊液中的多肽和蛋白质进行鉴定的方法。我们将使用专有的生物信息学来识别和定量代谢物，肽，蛋白质质谱。目的二提出确定特定的候选生物标志物相关的潜在的病理生理过程中已知或假设参与AD，特别是泛素蛋白酶体系统（UPS）。我们将开发条件，以模拟AD使用蛋白酶体抑制在啮齿动物原代神经元细胞培养，因为蛋白酶体抑制被怀疑发生作为一个早期事件在AD病理。我们将使用各种亲和技术来捕获由于UPS抑制而积累的肽或蛋白质。捕获的蛋白质将通过MS鉴定，并添加到推定的生物标志物列表中。总之，这些研究将证明我们广泛的表型分析方法在鉴定和定量生物标志物方面的可行性，并为我们提供用于人CSF样品研究的经验证的方法和工具。 拟定商业应用：我们建议开发一个全球性的蛋白质组学分析解决方案，使用一个创新的技术平台来探测阿尔茨海默病（AD）的分子特征。该分析将与专有的生物信息学相结合，以识别和验证AD的推定生物标志物。 该研究计划将导致诊断试剂盒，治疗靶点，仪器和生物信息学的商业化。

DESCRIPTION (provided by applicant): Biomarkers are urgently needed for the early and accurate diagnosis of Alzheimer's disease (AD). SurroMed is using a high throughput, multiplexed proteomics approach to detect, identify and quantify a large number of putative biomarkers in animal models and human cerebrospinal fluid (CSF) specimens. Aim I proposes to develop methods to fractionate CSF and identify peptides and proteins in CSF using micro-scale liquid chromatography and mass spectrometry (MS). We will use proprietary bioinformatics to identify and quantify metabolites, peptides, proteins in mass spectra. Aim II proposes to identify specific candidate biomarkers related to underlying pathophysiological processes with known or hypothesized involvement in AD, specifically the ubiquitin proteasome system (UPS). We will develop conditions to simulate AD using proteasome inhibition in rodent primary neuronal cell cultures since proteasome inhibition is suspected to occur as an early event in AD pathology. We will use a variety of affinity techniques to capture peptides or proteins that accumulate due to UPS inhibition. Captured proteins will be identified by MS, and added to a list of putative biomarkers. Taken together, these studies will demonstrate the feasibility of our broad phenotypic analysis approach to identifying and quantifying biomarkers and provide us with validated methods and tools for studies of human CSF samples. PROPOSED COMMERCIAL APPLICATION: We propose to develop a global solution for proteomic analysis using an innovative technology platform for probing the molecular signatures of Alzheimer's disease (AD). The analysis will be coupled with proprietary bioinformatics to identify and validate putative biomarkers for AD. This research program will lead to commercialization of diagnostic kits, therapeutic targets, instrumentation, and bioinformatics.