Understanding of the interactions of genes, immune responses, and environmental factors that induce pancreatic and allow its progression to type 1 diabetes (T1D) requires that the pathogenic process be identified from its onset. We hypothesize that the initiation of the autoimmune cascade and the resultant molecular and cellular changes that culminate in insulin deficiency, occur in the very early years of life. Only recently with the advent of high throughput genotyping technologies has the hypothesis become testable. In the first 4 years of our prospective assessment in newborns for diabetes autoimmunity (PANDA), we have screened >8,000 newborns from the general population and followed a cohort of ~300 high-risk infants whose HLA genotype puts them at high risk for developing diabetes. In addition, we have screened ~800 relatives of T1D-affected patients and are closely following 415 of them with high/moderate risk HLA genotypes. We seek to further define our preliminary findings of genetic, immunological, and environmental factors that may contribute to T1D pathogenesis. We propose four specific aims: 1) Expand to 23,000, the number of newborns screened from the general population and increase to 2,500, the number of HLA-typed relatives of T1D patients. 2) Monitor the appearance of beta cell autoimmunity (BCA) and its progression to T1D in children with high-risk genotypes, specifically examining the frequency, timing and order of appearance of Ab (GAD, IA2, IAA & ICA) beginning at 6 months of age and then at regular intervals (3-6 months) thereafter. We will also conduct questionnaire-guided interviews to collect detailed data on demographics, family history of autoimmunity, prenatal and neonatal exposures, infant diet, daycare, psychological stressors, and immunization to assess the impact of potential environmental factors, which may trigger or modify the autoimmune process. 3) Investigate the roles of pro-inflammatory prostaglandins on BCA. We will study the natural history of prostaglandin synthase-2 (PGS2) expression by monocytes, assess its predictive value for B-cell autoimmunity, and will seek confirmation of the observed association between a modulator of PGS-2 activity - dietary n-3 polyunsaturated fatty acids - and BCA by analyzing erythrocyte membrane fatty acid levels in Ab+ subjects and matched controls. 4) One of our novel and exciting findings derived from the high throughput microarray technology is the unique expression profiles of some 200 genes that associate with serum Ab positivity. This high-risk profile also occurs in ~25% of children under 3 years old who are Ab-, but who are HLA-DR3/4 and have a relative with T1D. This rate approximates the lifetime diabetes risk of these children. We now seek validation of the observed association in additional subjects after longer follow-up and we will determine the utility (specificity and sensitivity) of RNA profiling for prediction of BCA and T1D. Since our new program will explore a previously inaccessible pre-clinical phase of T1D, our studies should provide novel insights that may advance new genetic and immunologic technologies for predicting and preventing the disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD037800-04
Application #
6544463
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Grave, Gilman D
Project Start
1999-09-07
Project End
2007-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$670,401
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Purohit, Sharad; Sharma, Ashok; Zhi, Wenbo et al. (2018) Proteins of TNF-? and IL6 Pathways Are Elevated in Serum of Type-1 Diabetes Patients with Microalbuminuria. Front Immunol 9:154
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
Purohit, Sharad; Sharma, Ashok; She, Jin-Xiong (2015) Luminex and other multiplex high throughput technologies for the identification of, and host response to, environmental triggers of type 1 diabetes. Biomed Res Int 2015:326918
Törn, Carina; Hadley, David; Lee, Hye-Seung et al. (2015) Role of Type 1 Diabetes-Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study. Diabetes 64:1818-29
Jin, Yulan; Sharma, Ashok; Bai, Shan et al. (2014) Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function. Diabetes 63:2506-15
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

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