BetaMarker: Biomarkers of Beta Cell Stress in Type 1 Diabetes
EMSL Project ID
48703
Abstract
Type 1 diabetes (T1D) is generally accepted to result from impaired immune tolerance, leading to the autoimmune destruction of islet beta cells. However, the durable preservation of beta cell function in clinical studies utilizing traditional immunomodulatory therapies has remained elusive. These disappointing outcomes suggest that earlier treatment, prior to frank metabolic decompensation, may yield better outcomes. A key unmet need in the field has been the discovery and validation of simple and reliable biomarkers that discriminate those who will progress or not to T1D. Recent studies suggest the provocative concept that stress pathways triggered within the beta cell very early in T1D evolution may initiate and/or accelerate autoimmune-mediated cell destruction. This overdue emphasis on the beta cell offers a unique opportunity to improve current T1D diagnostic strategies. This application is based on the hypothesis that stressed beta cells of pre-diabetic individuals liberate specific protein and DNA species into plasma, and that measurement of multiple such species can define the beta cell "stress signature" that confers risk for developing T1D. To test this hypothesis, we have assembled an interactive team of scientists that will collectively engage its proteomics, functional genomics, islet expertise, and bioinformatics/statistics to identify protein and nucleic acid-derived biomarkers emanating from stressed beta cells that can stratify better the risk of developing T1D. This project, called "BetaMarker," will follow a two-pronged approach: a focused, approach based on candidate protein and nucleic biomarkers already identified by our team that will be tested in populations at-risk for T1D, and a proteomics and nucleic acid-based discovery approach aiming to identify novel biomarkers.
Project Details
Start Date
2015-01-19
End Date
2017-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Colli M.L., M. Ramos-Rodriquez, E.S. Nakayasu, M.I. Alvelos, M. Lopes, J.L. Hill, and J. Turatsinze, et al. 2020. "An integrated multi-omics approach identifies the landscape of interferon-a-mediated responses of human pancreatic beta cells." Nature Communications 11. PNNL-SA-144581. doi:10.1038/s41467-020-16327-0
Nakayasu E.S., F. Syed, S. Tersey, M.A. Gritsenko, H.D. Mitchell, C. Chan, and J. Turatsinze, et al. 2020. "Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention." Cell Metabolism 31, no. 2:363-374.e6. PNNL-SA-150166. doi:10.1016/j.cmet.2019.12.005
02/04/2020
Romas-Rodriquez M., H. Raurell-Vila, M.L. Colli, M.I. Alvelos, M. Subirana, J.J. Mateu, and R. Norris, et al. 2019. "The impact of pro-inflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes." bioRxiv. PNNL-SA-141684. doi:10.1101/560193.