Next Generation Translational Proteomics for Alzheimer's and Related Dementias

阿尔茨海默氏症和相关痴呆症的下一代转化蛋白质组学

• 批准号: 10573244
• 负责人: Michael MacCoss
• 金额: $ 314.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573244
• 关键词: Acceleration; Adoption; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid deposition; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Proteins; Brain; Brain Mapping; Brain region; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Chronic Disease; Clinical; Compensation; Complement; Consensus; Consumption; Custom; Data; Dementia; Detection; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Flow Cytometry; Functional disorder; Genetic Risk; Goals; Human; Impaired cognition; Individual; Infrastructure; Injury; Intercellular Fluid; Lipoproteins; Liquid substance; Logic; Mass Spectrum Analysis; Medicine; Methods; Mission; Molecular; Molecular Profiling; Monitor; Multiplexed Ion Beam Imaging; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Injury; Neuropsychological Tests; Neurosciences; Pathogenicity; Pathologic; Pathway interactions; Patients; Peripheral; Process; Protein Engineering; Proteins; Proteomics; Protocols documentation; Public Health; Reagent; Reproducibility; Research; Research Personnel; Resources; Sampling; Specimen; System; Technology; Transportation; United States National Institutes of Health; Validation; Work; clinical diagnostics; clinically relevant; data dissemination; data sharing; diagnostic value; extracellular vesicles; improved; in vivo; innovation; molecular imaging; new technology; next generation; novel; outcome prediction; particle; precision medicine; programs; protein biomarkers; response to injury; therapeutic target; translational applications; translational proteomics; treatment response

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.

摘要 阿尔茨海默病（Alzheimer's disease，AD）是一个日益严重的全球性公共卫生问题。这是一个令人生畏的科学 挑战和解决办法只能来自创新研究。我们带来了一个独特的 一个跨学科的研究团队，目标是弥合最先进技术之间的鸿沟 和翻译应用。 为了监测AD疾病进展或对治疗的反应，脑脊液（CSF）代表了AD患者的血液。 首选液体，以反映大脑病理生理学。脑间质液与CSF直接接触， 蛋白质和CSF的不受限制的双向流动受到保护，不受外周系统的影响， 𝛽 血脑屏障限制分子和蛋白质的运输。已知的CSF生物标志物有 已被证明反映了AD脑中发生的三种主要病理变化-淀粉样蛋白- 沉积、神经元变性和神经元损伤。因此，分析分子和粒子在 CSF在改善神经退行性疾病的诊断和表征方面具有最大的潜力 in vivo. 我们建议通过制定一项合作研究计划， 一个独特的研究团队，其具体目标是极大地改善CSF的分子特征， 认知能力下降和AD病理生理学的预测因子。该计划将补充现有的 努力加速临床相关治疗靶点的鉴定和验证。我们将在 与加速药物伙伴关系（AMP）和AD中心计划等计划并行， 独特的诊断能力，支持将新药带给患者的过程。 我们的U19研究计划将包括四个项目和四个核心，这是协同我们的使命。 此外，我们的研究团队非常适合开发，验证和翻译应用， 反映AD病理生理学的新生物分子测定。这一U19将利用集体的专业知识， 多个领域，结合足够的财政资源来扩展和应用下一代蛋白质组学 技术应用于临床标本，这些临床标本已被广泛注释， 诊断和神经心理学测试数据。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的和可持续的试剂，以促进传播和部署， 这些方法在世界范围内。我们的计划将扩展我们实验室开发的现有基础设施， 并传播这些数据和协议。新技术的应用，新产品的开发 试剂、新的临床检测方法的创建以及数据和协议的传播将加速神经科学的发展。 这在传统的NIH机制下是不可行的。