Development of biomarkers in peripheral blood that could predict onset of type 1 diabetes

Pang, Dimeng (2013). Development of biomarkers in peripheral blood that could predict onset of type 1 diabetes PhD Thesis, University of Queensland Diamantina Institute, The University of Queensland. doi:10.14264/uql.2014.129

       
Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
s4214135_phd_submission_final.pdf Thesis(fulltext) application/pdf 2.61MB 9

Author Pang, Dimeng
Thesis Title Development of biomarkers in peripheral blood that could predict onset of type 1 diabetes
School, Centre or Institute University of Queensland Diamantina Institute
Institution The University of Queensland
DOI 10.14264/uql.2014.129
Publication date 2013
Thesis type PhD Thesis
Supervisor Professor Ranjeny Thomas
Emma Hamilton-Williams
Mark Harris
Total pages 174
Language eng
Subjects 1107 Immunology
Formatted abstract
In the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), genetically identical mice raised in the same environment develop diabetes at different rates. While much is known about the immune responses in this strain which predispose to T1D, there are no known predictors of disease progression. A similar lack of markers exists for progression to T1D in the pre-clinical phase in humans. Definition of such markers in mice would aid understanding of the mechanism of progression and may be translatable to children at risk. Since peripheral blood (PB) is readily accessible, I analysed serial PB samples in NOD mice over the T1D prodrome then scored pancreatic insulitis at 14 weeks or determined age of diabetes onset. Myeloid cell-driven inflammation is negatively associated with insulitis severity, but different mechanisms operate in overt diabetes onset. I therefore profiled gene expression in PB of 10-week NOD mice and determined age of diabetes onset. NOD mice developing diabetes before 18 weeks of age could be distinguished from late onset and non-diabetics by a signature of downregulated PB genes. Expression of several of these in PB at 10 weeks correlated significantly with age of diabetes onset. Gene expression was translated to a clinical cohort of first-degree relatives (FDRs) and T1D patients where expression of several genes differed significantly in islet antibody-negative, antibody-positive FDRs and diabetic individuals. The PB predictive markers facilitate identification of pre-clinical functional immune phenotypes in NOD mice destined for accelerated diabetes onset, and for validation in human cohorts of progressors and non-progressors to T1D. To directly determine β-cell death in the pathogenesis of T1D, I optimised in mice and human a published noninvasive protocol which detects β-cell death by the methylation status of serum insulin DNA. By tracking individual mice to diabetes, and separating a human cohort based on their number of autoantibodies, I demonstrate new insights into the rate of β-cell death in diabetes progression. Together, these findings identify novel biomarkers in blood and better understanding of β-cell death in the development of type 1 diabetes.
Keyword Biomarkers
Serum
Methylation
Cytokines
Type 1 diabetes
Microarray
Insulitis
Blood

 
Citation counts: Google Scholar Search Google Scholar
Created: Mon, 09 Jun 2014, 13:35:36 EST by Dimeng Pang on behalf of Scholarly Communication and Digitisation Service