This work is built on the hypothesis that molecular phenotyping (transcriptome and proteorhe characterization) will produce new insights into the pathogenesis of autoimmune diabetes in the Non Obese Diabetic (NOD) mouse at age 2-4 weeks. The very early pathogenic events may be particularly well suited for molecular characterization, because they may not be prominent enough to manifest themselves at the cellular/histological level. The initial work on this project has revealed promising new discoveries both regarding unique defects in the islet tissue (reduced oxidative stress defenses and increases in cell turn- over) and more universal defects present in both islets and immune cells (alterations in ribosomes and mitochondria). In this competitive renewal application we propose to shift the focus from islets of Langerhans to lymphocytes. We will characterize lymphocytes in great details. We believe it is important to conduct molecular characterization of a number of leukocyte subsets individually, to gain a detailed insight into the very early molecular signatures and immune system defects associated with the initiation of autoimmunity in NOD mice.
The specific aims of this proposal are:
Specific Aim 1. To compare the transcriptomes of spleen leukocyte subsets in NOD, NOR, and C57BL/6 female mice between 2 and 4 weeks of age (Specifically the B-lymphocytes, CD4 positive T-lymphocytes, CDS positive T-lymphocytes, and NK cells.
Specific Aim 2. To compare the proteomes of spleen leukocyte subsets in NOD, NOR, and C57BL/6 female mice between 2 & 4 weeks of age (looking at whole cells and subcellular fractions with a variety of proteome characterization approaches).
Specific Aim 3. To reveal molecular network associations between specific proteins and gene expression by conducting cluster analysis on combined molecular phenotype data files (using and further developing some novel analysis and mining approaches).
Specific Aim 4. To develop a public database for molecular phenotypes (to providing an easy-to-access and searchable portal to all of our data). Relevance to Public Health: This project aims to define the molecular defects responsible for the process that causes type 1 diabetes (also called insulin dependent or juvenile onset diabetes). With a better understanding of these processes it will be possible to develop interventions that prevent this disease. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Sechi, Salvatore
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University of Tennessee Health Science Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Kakoola, Dorothy N; Curcio-Brint, Anita; Lenchik, Nataliya I et al. (2014) Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes. Results Immunol 4:30-45
Gerling, Ivan C; Ahokas, Robert A; Kamalov, German et al. (2013) Gene Expression Profiles of Peripheral Blood Mononuclear Cells Reveal Transcriptional Signatures as Novel Biomarkers for Cardiac Remodeling in Rats with Aldosteronism and Hypertensive Heart Disease. JACC Heart Fail 1:
Gerling, Ivan C; Ahokas, Robert A; Kamalov, German et al. (2013) Gene expression profiles of peripheral blood mononuclear cells reveal transcriptional signatures as novel biomarkers of cardiac remodeling in rats with aldosteronism and hypertensive heart disease. JACC Heart Fail 1:469-76
Wu, Jian; Kakoola, Dorothy N; Lenchik, Nataliya I et al. (2012) Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes. PLoS One 7:e46941
Gupta-Ganguli, Malini; Cox, Kyle; Means, Blake et al. (2011) Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 34:e121
Solomon, S S; Odunusi, O; Carrigan, D et al. (2010) TNF-alpha inhibits insulin action in liver and adipose tissue: A model of metabolic syndrome. Horm Metab Res 42:115-21
Wang, Xiaofei; Nookala, Suba; Narayanan, Chidambarathanu et al. (2009) Proteomic analysis of the retina: removal of RPE alters outer segment assembly and retinal protein expression. Glia 57:380-92
Wu, Jian; Lenchik, Nataliya I; Gerling, Ivan C (2008) Approaches to reduce false positives and false negatives in the analysis of microarray data: applications in type 1 diabetes research. BMC Genomics 9 Suppl 2:S12
Gerling, Ivan C; Singh, Sudhir; Lenchik, Nataliya I et al. (2006) New data analysis and mining approaches identify unique proteome and transcriptome markers of susceptibility to autoimmune diabetes. Mol Cell Proteomics 5:293-305
Wu, Jian; Marler, Jacob; Lenchik, Nataliya I et al. (2006) Strain differences in allele and expression levels of CD72 on B-lymphocytes from NOD, AKR, NON and C57BL/6 mice. Immunol Lett 103:115-20

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