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Serum biomarkers for predicting type 1 diabetes


EMSL Project ID
50077

Abstract

Clinical type 1 diabetes (T1D) is preceded by an asymptomatic phase of the disease, which can be readily identified by serum islet autoantibodies(AAb). However, the T1D field is challenged by the lack of potent predictive markers, particularly beta-cell specific serum markers that can accurately predict and reveal the rate of T1D progression. The markers of such are critical in the development of novel and effective interventions for T1D. Therefore, the overall objective of this application is to establish beta-cell specific serum proteomic signatures that can predict the immunogenic progression of T1D. Our specific hypothesis is that the ongoing autoimmune destruction of beta-cells during the pre-T1D phase sheds beta-cell-specific protein signatures into the blood stream, and these circulatory signatures are suitable biomarkers for assessing beta-cell mass, predicting the trajectory of beta-cell destruction and thus the developmental stage of T1D. To pursue this objective, our rationale is to apply a hypothesis-focused integrative discovery approach to comprehensively identify putative beta-cell specific proteins, isoforms, and posttranslational modifications (PTMs) from pancreatic islets and tissues. Protein candidates are then prioritized and validated in the serum samples collected from large-scale longitudinal clinical studies such as the Diabetes Prevention Trial (DPT-1) via the implementation of an ultrasensitive targeted proteomic technology. The availability of a set of islet-specific proteins (already identified through our preliminary studies) and the unique ultrasensitive technology provides us a first-rate opportunity to establish novel predictive serum markers for T1D development. In our experimental plan, Aim 1 will focus on the integrative discovery of putative beta-cell specific proteins, isoforms, and PTMs by comparing pre-T1D versus control pancreas and islets. Aim 2 will conduct an initial screening for the top 100-200 candidates based on their detectability in human serum as well as their significant differential serum concentration in new-onset T1D subjects versus controls. Aim 3 will perform targeted validation of the most promising 10-30 candidates in the serum samples longitudinally collected in the DPT-1 cohort. The comparison will include three groups of subjects: 1) T1D relatives who had multiple AAb and progressed to T1D 2) T1D relatives who had multiple AAb but did not progress to T1D, and 3) AAb negative controls. We anticipate this application will enable us for the first time to successfully develop a panel of beta-cell specific serum markers, which will have a profound clinical implication for predicting T1D progression, assessing beta-cell mass, and monitoring the treatment efficacy.

Project Details

Start Date
2017-10-24
End Date
2020-09-30
Status
Closed

Team

Principal Investigator

Weijun Qian
Institution
Pacific Northwest National Laboratory

Team Members

Zhangyang Xu
Institution
Pacific Northwest National Laboratory

Tong Zhang
Institution
Pacific Northwest National Laboratory

Adam Swensen
Institution
Pacific Northwest National Laboratory

Marina Gritsenko
Institution
Pacific Northwest National Laboratory

Rohit Kulkarni
Institution
Joslin Diabetes Center

Related Publications

Dirice E., S. Kahraman, D.F. De Jesus, A. El Ouaamari, G. Basile, R. Baker, and B. Yigit, et al. 2019. "Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes." Nature Metabolism 1. PNNL-SA-141695. doi:10.1038/s42255-019-0061-8
Gupta M., D.F. De Jesus, S. Kahraman, I. Valdez, L. Yi, A.C. Swensen, and Y. Tseng, et al. 2018. "Insulin Receptor Mediated Signaling Regulates Pluripotency Markers and Lineage Differentiation." Molecular Metabolism 18. PNNL-SA-136923. doi:10.1016/j.molmet.2018.09.003
Sims E.K., H.T. Bahnson, J. Nyalwidhe, L. Haataja, A.K. Davis, C. Speake, and L.A. DiMeglio, et al. 2019. "Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes." Diabetes Care 42, no. 2:258-264. PNNL-SA-140217. doi:10.2337/dc17-2625
Wang X., A.C. Swensen, T. Zhang, P.D. Piehowski, M.J. Gaffrey, M.E. Monroe, and Y. Zhu, et al. 2020. "Accurate Identification of Deamidation and Citrullination from Global Shotgun Proteomics Data Using a Dual-search Delta Score Strategy." Journal of Proteome Research 19, no. 4:1863-1872. PNNL-SA-149222. doi:10.1021/acs.jproteome.9b00766
Yi L., C. Tsai, E. Dirice, A.C. Swensen, J. Chen, T. Shi, and M.A. Gritsenko, et al. 2019. "Boosting to Amplify Signal with Isobaric Labeling (BASIL) Strategy for Comprehensive Quantitative Phosphoproteomic Characterization of Small Populations of Cells." Analytical Chemistry 91, no. 9:5794-5801. PNNL-SA-140381. doi:10.1021/acs.analchem.9b00024
Yi L., T. Shi, M.A. Gritsenko, C. Chan, T.L. Fillmore, B.M. Hess, and A.C. Swensen, et al. 2018. "Targeted Quantification of Phosphorylation Dynamics in the Context of EGFR-MAPK Pathway." Analytical Chemistry 90, no. 8:5256-5263. PNNL-SA-131519. doi:10.1021/acs.analchem.8b00071
Zhao Y., C. Shanshuang, A.C. Swensen, W. Qian, and E. Gouaux. 2019. "Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM." Science 364, no. 6438:355-362. PNNL-SA-141540. doi:10.1126/science.aaw8250
Zhu Y., M. Dou, P.D. Piehowski, Y. Liang, F. Wang, R.K. Chu, and W.B. Chrisler, et al. 2018. "Spatially Resolved Proteome Mapping of Laser Capture Microdissected Tissue with Automated Sample Transfer to Nanodroplets." Molecular and Cellular Proteomics 17, no. 9:1864-1874. PNNL-SA-138815. doi:10.1074/mcp.TIR118.000686