Type 1 diabetes (T1D) results from poorly defined interactions between susceptibility genes, the environment, and the immune system. The long presymptomatic period, during which a series of islet-cell antigen-specific autoantibodies (Ab), activated T-cells and other molecular changes arise, provides an opportunity for disease prevention. Accurate risk assessment is vital for disease prevention so that therapy can be given to those individuals who are very likely to develop the disease. Despite the identification of several useful disease markers such as autoantibodies, there is still an urgent need for more specific and earlier T1D markers. Unfortunately, progress has been very slow until the recent developments of novel genomic tools. By expression profiling of peripheral blood lymphocytes, we identified several hundred genes that are differentially expressed in Ab negative (AbN) controls versus T1D patients and Ab positive (AbP) subjects. Using multivariate models of gene expression, we identified two AbP subsets who have different progression rates to T1D, suggesting that expression profiling may be very powerful T1D markers. In the R21 phase, we will carry out a cross-sectional study to confirm our preliminary findings and to develop novel biomarkers for accurate risk assessment for the transition from AbP to T1D as well as from AbN to AbP stages. Once the feasibility is demonstrated in the R21 phase, we will validate, in the R33 phase, the novel biomarkers in a prospective data set. We will also develop and validate highly reproducible and economic assays for efficient measurement of these biomarkers and the new assays will be tested in two large population screening programs (PANDA and DAISY) that have been underway in the investigators' laboratory. These step-wise studies are designed to develop and validate novel biomarkers and bring them to clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33DK069878-03
Application #
7110728
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Program Officer
Akolkar, Beena
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$380,472
Indirect Cost
Name
Georgia Health Sciences University
Department
Pathology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Purohit, Sharad; Sharma, Ashok; Hopkins, Diane et al. (2015) Large-Scale Discovery and Validation Studies Demonstrate Significant Reductions in Circulating Levels of IL8, IL-1Ra, MCP-1, and MIP-1? in Patients With Type 1 Diabetes. J Clin Endocrinol Metab 100:E1179-87
Sharma, Shruti; Purohit, Sharad; Sharma, Ashok et al. (2015) Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes. Mediators Inflamm 2015:279393
Jin, Yulan; Sharma, Ashok; Carey, Colleen et al. (2013) The expression of inflammatory genes is upregulated in peripheral blood of patients with type 1 diabetes. Diabetes Care 36:2794-802
Lu, Shangsu; Purohit, Sharad; Sharma, Ashok et al. (2012) Serum insulin-like growth factor binding protein 6 (IGFBP6) is increased in patients with type 1 diabetes and its complications. Int J Clin Exp Med 5:229-37
Jin, Yulan; Purohit, Sharad; Chen, Xueqin et al. (2012) Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4(+)CD25(+) regulatory T cells. Biochem Biophys Res Commun 424:669-74
Jin, Yulan; She, Jin-Xiong (2012) Novel biomarkers in type 1 diabetes. Rev Diabet Stud 9:224-35
Guan, Ruili; Purohit, Sharad; Wang, Hongjie et al. (2011) Chemokine (C-C motif) ligand 2 (CCL2) in sera of patients with type 1 diabetes and diabetic complications. PLoS One 6:e17822
Reddy, M V Prasad Linga; Wang, H; Liu, S et al. (2011) Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. Genes Immun 12:208-12
Zhi, Wenbo; Sharma, Ashok; Purohit, Sharad et al. (2011) Discovery and validation of serum protein changes in type 1 diabetes patients using high throughput two dimensional liquid chromatography-mass spectrometry and immunoassays. Mol Cell Proteomics 10:M111.012203
Carey, Colleen; Purohit, Sharad; She, Jin-Xiong (2010) Advances and challenges in biomarker development for type 1 diabetes prediction and prevention using omic technologies. Expert Opin Med Diagn 4:397-410

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