snoRNAs in Complications of Type 1 Diabetes
High circulating levels of metabolites cause diabetic complications through the generation of oxidative stress. We recently discovered that intronic small nucleolar RNAs (snoRNAs) play a critical role in metabolic and oxidative stress-induced cell death in cultured cells and animal models. Our data are the first to ascribe a function for snoRNAs in the regulatory networks of a pathophysiological response. Because these sequences are non-coding and often intronic, there is little data on variation in the snoRNAs in humans. In this project we will develop the methodology to systematically sequence human snoRNAs to understand the degree of conservation or variation. By comparing snoRNA sequences in diabetics with and without microvascular complications and in the publically available 1000 Genomes database, we will test the hypothesis that rare variation snoRNAs is associated with protection from diabetic complications.

The role of TLR-mediated inflammation in diabetic cardiomyopathy
Cardiovascular disease is the leading cause of death in diabetics who suffer from aggressive atherosclerosis and cardiomyopathy. Inflammation is now recognized as a central feature of obesity, insulin resistance, and diabetes. Nonetheless, the role of inflammatory pathways in the pathogenesis of diabetic cardiac dysfunction has been largely unexplored. Evidence is emerging that Toll-like receptor (TLR) 4 and 2, originally identified as host receptors for bacterial lipids and lipoproteins such as lipopolysaccharide (LPS), contribute to systemic insulin resistance in lipid overload states through a mechanism that may involve activation by saturated fatty acids. Our preliminary studies demonstrate alterations in myocardial lipid metabolism can activate inflammatory signaling in vivo. We will use mouse models of lipotoxic cardiomyopathy and diabetic cardiomyopathy combined with TLR4 and TLR2 loss of function to test the hypothesis that TLR-mediated inflammatory signaling contributes to the pathogenesis of diabetic cardiac dysfunction.

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