The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes

Frontiers in Endocrinology

Endocrinology

Yury O. Nunez Lopez¹  Ananya Bhatheja¹  Christopher Clifford¹  Alejandra M. Petrilli¹  Elvis Alvarez Carnero¹  Heather Cornnell¹  Anika Bilal¹  Karen D. Corbin¹  Anna Casu¹  Gongxin Yu¹  Richard E. Pratley¹  Anton Iliuk²  David M. Maahs³ 

[1] AdventHealth, Translational Research Institute (TRI), Orlando, FL, United States;Biomarker Discovery Department, Tymora Analytical Operations, West Lafayette, IN, United States;Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States;

关键词: extracellular vesicles;    proteomics;    phosphoproteomics;    type 1 diabetes;    human;   

DOI  :  10.3389/fendo.2023.1219293

 received in 2023-05-08, accepted in 2023-07-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThere are no validated clinical or laboratory biomarkers to identify and differentiate endotypes of type 1 diabetes (T1D) or the risk of progression to chronic complications. Extracellular vesicles (EVs) have been studied as biomarkers in several different disease states but have not been well studied in T1D.MethodsAs the initial step towards circulating biomarker identification in T1D, this pilot study aimed to provide an initial characterization of the proteomic and phosphoproteomic landscape of circulating EV-enriched preparations in participants with established T1D (N=10) and healthy normal volunteers (Controls) (N=7) (NCT03379792) carefully matched by age, race/ethnicity, sex, and BMI. EV-enriched preparations were obtained using EVtrap® technology. Proteins were identified and quantified by LC-MS analysis. Differential abundance and coexpression network (WGCNA), and pathway enrichment analyses were implemented.ResultsThe detected proteins and phosphoproteins were enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 proteins and 8 phosphoproteins were differentially abundant in participants with T1D compared to controls, including some well-known EVproteins (i.e., CD63, RAB14, BSG, LAMP2, and EZR). Enrichment analyses of differentially abundant proteins and phosphoproteins of EV-enriched preparations identified associations with neutrophil, platelet, and immune response functions, as well as prion protein aggregation. Downregulated proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, HLA-DRB1, CD74, NUCB1, and SAP, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others.DiscussionThis study demonstrates the potential of proteomic and phosphoproteomic signatures of EV-enriched preparations to provide insight into the pathobiology of T1D. The WGCNA analysis could be a powerful tool to discriminate signatures associated with different pathobiological components of the disease.

【 授权许可】

Unknown   
Copyright © 2023 Casu, Nunez Lopez, Yu, Clifford, Bilal, Petrilli, Cornnell, Carnero, Bhatheja, Corbin, Iliuk, Maahs and Pratley