Evaluation of the specificity and early diagnostic value of novel peptide biomarkers of Type 1 Diabetes
EMSL Project ID
46703
Abstract
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic B-cells triggered by complex interactions of environmental factors in genetically predisposed individuals. Current autoantibody assays used to predict progression and confirm clinical diagnoses of T1D suffer from sometimes poor inter-laboratory reproducibility and prediction power. Using liquid chromatography-mass spectrometry (LC-MS) based proteomics analyses of human blood serum/plasma, we recently identified a panel of novel peptides and proteins having very good discriminating power of T1D from healthy controls. These novel peptide/protein biomarkers implicate dysregulated innate immune response in the development of T1D and may provide additional insight into the pathogenesis of T1D. Based on our preliminary data, these analyses are more accurate and precise than the currently available autoantibody measurements. However, the Diabetes Antibody Standardization Program (DASP) cohort used in our study was limited in sample size. Although similar clinical outcomes are shared between type 1 and type 2 diabetes, and there are other autoimmune diseases having similar immune and inflammatory dysfunction as T1D, our hypothesis is that some of these novel innate immunity peptide/protein markers are specific to T1D only. Therefore, by measuring these biomarkers in blood serum/plasma from independent, large scale T1D cohorts, as well as from individuals having diseases that share similar clinical and biochemical outcomes with T1D, we can 1) confirm the utility and specificity of these peptide/protein markers for diagnosing T1D, 2) gain further insight into the pathogenesis of this disease, and 3) evaluate the prognostic value of validated marker peptides. The results of these efforts can provide the clinical community with thoroughly validated peptide/protein markers that are of high diagnostic value, as well as provide foundations for new strategies in T1D prognosis, intervention and prevention. To accomplish these goals, we propose the following specific aims:
Aim 1. Establish the specificity of marker peptides. Serum samples from type 2 diabetes (50 samples), impaired glucose tolerance (50 samples), and Crohn's disease (50 samples) - diseases that share similar clinical outcomes or dysregulated immune and inflammatory responses with T1D - will be measured using LC-MRM-MS to evaluate the specificity of these peptide markers in diagnosing T1D. In addition, samples from individuals with persistent high levels of islet autoantibodies but who have not developed T1DM (50 samples) will be analyzed.
Aim 2. Establish the prognostic value of validated marker peptides. Longitudinal samples (5 time points) from 25 T1D patients will be measured using the LC-MRM-MS assay to establish correlation between the abundance of validated marker peptides, disease progression and the persistence of islet autoantibody positivity.
Project Details
Start Date
2012-02-10
End Date
2014-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Townsend P, Q Zhang, J Shapiro, BJM Webb-Robertson, LM Bramer, AA Schepmoes, KK Weitz, M Mallette, H Moniz, R Bright, Z Samad, T Kamphaus, SA Shah, BE Sands, and N Leleiko. 2015. "Serum Proteome Profiles in Stricturing Crohn’s Disease: A pilot study." Inflammatory Bowel Diseases. doi:10.1097/MIB.0000000000000445 [In Press]
Zhang Q, TL Fillmore, AA Schepmoes, TRW Clauss, MA Gritsenko, PW Mueller, M Rewers, MA Atkinson, RD Smith, and TO Metz. 2012. "Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes." The Journal of Experimental Medicine. doi:10.1084/jem.20111843