Next Generation Translational Proteomics for Alzheimer's and Related Dementias

摘要 阿尔茨海默病(AD)是一个日益严重的全球公共卫生问题。这是一项令人生畏的科学 挑战和解决方案只会来自创新研究。我们带来了一个独一无二的 跨学科的研究团队，目标是弥合尖端技术之间的鸿沟 和翻译应用程序。 为了监测AD疾病的进展或治疗反应，脑脊液(CSF)代表 首选液体以反映大脑的病理生理。脑间质液体通过以下方式与脑脊液直接接触 不受限制的蛋白质双向流动和脑脊液受到保护，不受外围系统的影响，因为 𝛽 通过血脑屏障限制分子和蛋白质的运输。已知的脑脊液生物标志物 已被证明反映了AD大脑中发生的三种主要病理变化--淀粉样蛋白-- 沉积、神经原纤维变性和神经元损伤。因此，对分子和粒子的分析 脑脊液具有最大的潜力来改善我们对神经退行性疾病的诊断和特征 在活体内。 我们建议通过开发一个联合起来的合作研究计划来实现AD的精准医学 一个独特的研究团队，其具体目标是极大地改善脑脊液AS的分子特征 认知衰退和阿尔茨海默病病理生理学的预测因子。这一计划的努力将补充现有的 努力加快确定和确认临床相关的治疗靶点。我们将在 与加速药物合作(AMP)和AD中心计划等计划并行，以提供 独特的诊断能力，支持向患者提供新药的过程。 我们的U19研究计划将由四个项目和四个核心组成，这些项目和核心对我们的使命是协同的。 此外，我们的研究团队非常适合开发、验证和翻译应用程序 反映AD病理生理学的新生物分子分析。这款U19将利用 多个领域，结合足够的财政资源来推广和应用下一代蛋白质组学 已被广泛注释为纵向的、一致的临床标本的临床标本技术 诊断和神经心理测试数据。我们将创建新的分析，目标是部署到 临床实验室。我们将创造独特和可持续的试剂，促进传播和部署 这些方法在全球范围内。我们的计划将扩展由我们的实验室开发的现有基础设施，用于共享 并传播这些数据和协议。新技术的应用，小说的发展 试剂、新的临床分析方法的创建以及数据和方案的传播将促进神经科学的发展 以一种在传统的NIH机制下不可行的方式。

Abstract Alzheimer's disease (AD) is a major, growing global public health problem. This is a daunting scientific challenge and solutions will come only from innovative research. We have brought together a unique interdisciplinary team of investigators with the goal of bridging the divide between state-of-the-art technologies and translational applications. To monitor AD disease progression or response to treatment, cerebrospinal fluid (CSF) represents the preferred fluid to reflect brain pathophysiology. The brain interstitial fluid is in direct contact with the CSF by unrestricted bidirectional flow of proteins and the CSF is protected from the peripheral system because of the 𝛽 restricted transportation of molecules and proteins by the blood-brain barrier. Known CSF biomarkers have been demonstrated to reflect the three main pathological changes that occur in the AD brain -- amyloid- deposition, neurofibrillary degeneration, and neuronal injury. Therefore, analysis of molecules and particles in CSF holds the greatest potential to improve our diagnosis and characterization of neurodegenerative diseases in vivo. We propose to enable precision medicine for AD by developing a cooperative research program that will unite a unique research team with the specific goal of vastly improving the molecular characterization of CSF as predictors of cognitive decline and AD pathophysiology. The efforts of this program will complement existing efforts to accelerate the identification and validation of clinically relevant therapeutic targets. We will work in parallel with programs like Accelerating Medicines Partnership (AMP) and the AD Centers Program, to provide unique diagnostic capabilities in support of the process of bringing new medicines to patients. Our U19 research program will consist of four projects and four cores that are synergistic to our mission. Moreover, our research team is uniquely suited to the development, validation and translational application of new biomolecular assays to reflect AD pathophysiology. This U19 will harness the collective expertise of multiple fields, combined with the financial resources sufficient to extend and apply next generation proteomics technologies to clinical specimens that have been extensively annotated with longitudinal, consensus clinical diagnostic and neuropsychological test data. We will create new assays with the goal of deployment to the clinical lab. We will create unique and sustainable reagents that will facilitate dissemination and deployment of these methods worldwide. Our program will expand existing infrastructure, developed by our labs, for sharing and disseminating these data and protocols. The application of new technologies, development of novel reagents, creation of new clinical assays, and dissemination of data and protocols will accelerate neuroscience in a way not feasible under traditional NIH mechanisms.