Dissecting signaling pathways and seeking EV phosphoproteins as novel biomarkers for Alzheimer's Disease

剖析信号通路并寻找 EV 磷蛋白作为阿尔茨海默病的新型生物标志物

• 批准号: 10399815
• 负责人: W. Andy Tao
• 金额: $ 12.34万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399815
• 关键词: Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer’s disease biomarker; Amyloid beta-Protein; Cells; Cerebral cortex; Characteristics; Clinical; Cognitive; Complement; Deposition; Detection; Deterioration; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Fibrin; Fluorescence; Goals; In Vitro; Mass Spectrum Analysis; Memory; Methods; Molecular; Molecular Disease; Monitor; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phosphoproteins; Phosphorylation; Phosphotransferases; Plasma; Play; Proteins; Proteomics; Research; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; United States National Institutes of Health; Validation; abeta deposition; biomarker discovery; clinical Diagnosis; disease diagnosis; driving force; early onset; extracellular vesicles; high throughput screening; hyperphosphorylated tau; innovation; novel; novel marker; novel strategies; tau Proteins; upstream kinase

PROJECT SUMMARY Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory deterioration. The characteristic pathology changes in AD are fibrin deposition in cerebral cortex, likely through the deposition of beta-amyloid (AE) in cell space and hyperphosphorylated Tau protein in cell. However, the exact molecular mechanism and pathogenic signaling of AD is not clear and researchers have been searching for new leads and reliable diagnosis for AD. In this R01 study that focuses on innovative and translational AD research, we will introduce novel strategies at the forefront of basic disease mechanism and clinical perspectives. The long term goal of this project is 1) to develop systematic strategies to dissect kinase-substrate signaling network related to onset of AD, with an emphasis on the identification and validation of direct kinase-substrate relationship in AD's critical pathogenic pathways; and 2) to develop phosphorylated proteins in plasma extracellular vesicles (EVs) for potential clinical diagnosis. As phosphorylation is a major player in early onset and progression of diseases such as AD, EV phosphoproteins are expected to become actively pursued targets as indicators of cellular states and for in vitro disease diagnosis. We will integrate novel proteomic approaches to identify AE and Tau upstream kinases associated with the pathogenesis of AD and to dissect AE and Tau- associated signaling networks. The strategy, fluorescence complementation mass spectrometry (FCMS), will utilize protein complementation and quantitative proteomics to establish a high throughput screening method to identify direct upstream kinases of AE and Tau associated with the AD progression. Accordingly, we will achieve the following specific aims: 1): Understanding the driving force of AD progression through the construction of high resolution kinase-substrate network in Aβ and Tau associated signaling pathways; 2): Establishment of an analytical platform for targeted detection of known AD biomarkers in plasma EVs; and 3): Discovery of phosphoproteins from plasma EVs as novel biomarkers for AD detection and monitoring.

项目概要 阿尔茨海默病（AD）是一种进行性、致命性的神经退行性疾病，表现为 认知和记忆力下降。 AD的特征性病理变化是纤维蛋白 大脑皮层中的沉积，可能是通过细胞空间中 β-淀粉样蛋白 (AE) 的沉积和 细胞中过度磷酸化的 Tau 蛋白。然而，确切的分子机制和致病机制尚不清楚。 AD 的信号传导尚不清楚，研究人员一直在寻找新的线索和可靠的线索 AD 的诊断。在这项专注于创新和转化 AD 研究的 R01 研究中，我们将 介绍基本疾病机制和临床观点前沿的新策略。 该项目的长期目标是 1) 制定系统策略来剖析激酶底物 与 AD 发病相关的信号网络，重点是识别和验证 AD 关键致病途径中的直接激酶-底物关系； 2）开发 血浆细胞外囊泡（EV）中的磷酸化蛋白用于潜在的临床诊断。作为 磷酸化是 AD、EV 等疾病早期发作和进展的主要因素 磷蛋白预计将成为积极追求的目标，作为细胞状态的指标 以及体外疾病诊断。我们将整合新的蛋白质组学方法来识别 AE 和 Tau 上游激酶与 AD 发病机制相关并剖析 AE 和 Tau- 相关的信令网络。策略，荧光互补质谱法 （FCMS），将利用蛋白质互补和定量蛋白质组学来建立高 通量筛选方法，用于鉴定与 AE 和 Tau 相关的直接上游激酶 AD进展。因此，我们将实现以下具体目标： 1）：了解 通过构建高分辨率激酶底物网络来驱动 AD 进展 Aβ 和 Tau 相关信号通路； 2）：建立分析平台 有针对性地检测血浆 EV 中已知的 AD 生物标志物； 3)：磷蛋白的发现 等离子 EV 作为 AD 检测和监测的新型生物标志物。

项目成果

Isolation and Identification of Plasma Extracellular Vesicles Protein Biomarkers.

血浆细胞外囊泡蛋白质生物标志物的分离和鉴定。

• DOI: 10.1007/978-1-0716-3163-8_14
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Lihon,MichelleV;Hadisurya,Marco;Wu,Xiaofeng;Iliuk,Anton;Tao,WAndy
• 通讯作者: Tao,WAndy

Data-Independent Acquisition Phosphoproteomics of Urinary Extracellular Vesicles Enables Renal Cell Carcinoma Grade Differentiation.

• DOI: 10.1016/j.mcpro.2023.100536
• 发表时间: 2023-05
• 期刊: MOLECULAR & CELLULAR PROTEOMICS
• 影响因子: 7
• 作者: Hadisurya, Marco;Lee, Zheng-Chi;Luo, Zhuojun;Zhang, Guiyuan;Ding, Yajie;Zhang, Hao;Iliuk, Anton B.;Pili, Roberto;Boris, Ronald S.;Tao, W. Andy
• 通讯作者: Tao, W. Andy

Uncovering ubiquitous protein lactylation.

发现普遍存在的蛋白质乳酰化。

• DOI: 10.1038/s41592-022-01536-w
• 发表时间: 2022
• 期刊: Nature methods
• 影响因子: 48
• 作者: Wu,Xiaofeng;Tao,WAndy
• 通讯作者: Tao,WAndy