The long-term goal of this project is to develop and apply the latest proteomics approaches to understand molecular dysfunction underlying the pathogenesis of Alzheimer's disease (AD). Dissection of molecular composition (e.g. DNAs, RNAs, and proteins) in clinical specimens is critical for understanding, detecting, preventing and treating disease. The evolving DNA technology has been revolutionizing medical research and patient care. National Institute on Aging has invested tens of millions of dollars to search for AD risk genes. In contrast, proteomic research is being left behind, largely due to the limitations of technology. Our lab has been developing proteomics approaches for ultra-sensitivity and high throughput for more than a decade. Recently, we have implemented a highly sophisticated platform for profiling more than 10,000 proteins. To explore the proteome alteration in human AD brains, we and collaborators initiated a study to analyze aggregated proteome, revealing unique U1 snRNP pathology in AD and raising a novel concept of RNA splicing alterations in the pathogenesis. Thus, we propose to further enhance the proteomics platform with milestones, and profile AD mouse and human brain proteomes, as well as the interactome of AD disease proteins, for identifying novel pathogenic mechanisms.
Three specific aims are: (i) to establish a multiplex, quantitative platform for nearly complete coverage of human proteome as well as comprehensive protein modification analyses, (ii) to identify aberrant protein pathways in AD by profiling the whole proteome and protein modifications in human and mouse models, and (iii) to determine AD disease pathways by the interactome of AD disease proteins in human. Successful outcome of this project will enable truly global proteomic studies of clinical samples, matching the coverage of genomics. The AD study may provide novel targets for pathogenesis and therapeutic intervention.

Public Health Relevance

Molecular analysis of specimens is essential for understanding, detecting, preventing and treating disease. Whereas human genomics is revolutionizing patient care, near complete proteome profiling has been emerging. We propose to develop multi-level integrative proteomics approaches and apply to dissect pathogenic mechanisms underlying Alzheimer's disease, the sixth leading cause of death in the United States.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (56)R)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Jude Children's Research Hospital
United States
Zip Code
Zeng, Hu; Yu, Mei; Tan, Haiyan et al. (2018) Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 4:eaar5701
Wang, Xusheng; Jones, Drew R; Shaw, Timothy I et al. (2018) Target-Decoy-Based False Discovery Rate Estimation for Large-Scale Metabolite Identification. J Proteome Res 17:2328-2334
Shen, Jianqiao; Pagala, Vishwajeeth R; Breuer, Alex M et al. (2018) Spectral Library Search Improves Assignment of TMT Labeled MS/MS Spectra. J Proteome Res 17:3325-3331
Xie, Boer; Wang, Yuanyuan; Jones, Drew R et al. (2018) Isotope Labeling-Assisted Evaluation of Hydrophilic and Hydrophobic Liquid Chromatograph-Mass Spectrometry for Metabolomics Profiling. Anal Chem 90:8538-8545
Bai, Bing; Tan, Haiyan; Peng, Junmin (2017) Quantitative Phosphoproteomic Analysis of Brain Tissues. Methods Mol Biol 1598:199-211
Niu, Mingming; Cho, Ji-Hoon; Kodali, Kiran et al. (2017) Extensive Peptide Fractionation and y1 Ion-Based Interference Detection Method for Enabling Accurate Quantification by Isobaric Labeling and Mass Spectrometry. Anal Chem 89:2956-2963
High, Anthony A; Tan, Haiyan; Pagala, Vishwajeeth R et al. (2017) Deep Proteome Profiling by Isobaric Labeling, Extensive Liquid Chromatography, Mass Spectrometry, and Software-assisted Quantification. J Vis Exp :
Tan, Haiyan; Yang, Kai; Li, Yuxin et al. (2017) Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity 46:488-503
Bai, B; Tan, H; Pagala, V R et al. (2017) Deep Profiling of Proteome and Phosphoproteome by Isobaric Labeling, Extensive Liquid Chromatography, and Mass Spectrometry. Methods Enzymol 585:377-395