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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要阿尔茨海默氏病（AD）是一种进行性和致命的神经退行性疾病认知和记忆恶化。 AD的特征病理变化是纤维蛋白脑皮质沉积，可能通过β-淀粉样蛋白（AE）在细胞空间中的沉积和细胞中的高磷酸化tau蛋白。但是，确切的分子机制和致病性广告的信号尚不清楚，研究人员一直在寻找新的潜在客户和可靠 AD诊断。在这项侧重于创新和翻译广告研究的R01研究中，我们将在基本疾病机制和临床观点的最前沿引入新型策略。该项目的长期目标是1）制定系统性策略以剖析激酶 - 覆盖物与AD发作有关的信号网络，重点是识别和验证 AD关键致病途径中的直接激酶 - 基底关系； 2）发展血浆细胞外蔬菜（EV）中的磷酸化蛋白质用于潜在的临床诊断。作为磷酸化是早期发作和疾病的进展（例如AD，EV）的主要参与者预计磷蛋白作为细胞状态的指标将积极追求靶标以及用于体外疾病诊断。我们将整合新颖的蛋白质组学方法来识别AE和 tau上游激酶与AD的发病机理相关，并剖析AE和Tau- 关联的信号网络。策略，荧光完成质谱法（FCMS），将利用蛋白质的完成和定量蛋白质组学来建立高吞吐量筛选方法以识别与与此相关的AE和TAU的直接上游激酶广告进展。根据，我们将达到以下特定目标：1）：了解通过建造高分辨率激酶 - 基底网络的AD进展的驱动力在Aβ和TAU相关的信号通路中； 2）：建立一个分析平台针对血浆电动汽车中已知的AD生物标志物的靶向检测；和3）：发现磷蛋白从等离子体电动汽车作为广告检测和监测的新型生物标志物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.)
影响因子：
0
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。