Increasing evidence strongly supports a role for inflammation in several cardiovascular complications associated with diabetes and obesity, including atherosclerosis. In studies funded by this grant, we made a major impact in the field by demonstrating for the first time the role of epigenetic mechanisms in inflammatory gene expression in monocytes under diabetic conditions. We also identified key active and repressive histone methyltransferases and associated chromatin modifications that co-operate with NF-kappaB to regulate specific inflammatory genes. However, our knowledge about the genome-wide spectrum of gene changes that occur under diabetic conditions is still very limited. Furthermore, recent evidence shows that majority of the genome is transcribed but is non-coding (i.e. does not encode proteins), and however still has the capacity to regulate gene expression. Thus epigenetic mechanisms also include regulatory events elicited by non-coding RNAs (ncRNAs). Thus our goal in this renewal is to now address this major gap in knowledge by deciphering how key gene networks and, for the first time novel long ncRNAs, promote monocyte /macrophage dysfunction under diabetic conditions. We will evaluate such new paradigms by testing the hypothesis that diabetic conditions lead to the mis-regulation of transcriptome networks of protein coding as well as non-coding transcripts that interact with chromatin factors and lead to enhanced inflammation, polarization and dysfunction in monocyte/macrophages. This is supported by new preliminary data from high throughput RNA-sequencing showing differential expression of novel transcripts in monocytes/macrophages under diabetic conditions.
Our Specific Aims will extend the preliminary results to first adopt RNA and chromatin profiling, in silico bioinformatics tools and experimental validation to determine the identities of coding and non-coding transcripts in macrophages from diabetic versus non-diabetic mice. We will then evaluate the functional roles of key candidate differentially expressed ncRNAs in mediating phenotypes of monocyte-macrophage dysfunction under diabetic conditions. The molecular mechanisms of action and regulation of the candidate long ncRNAs will then be determined. These significant and innovative studies combine genomic profiling and bioinformatics with in vivo models, mechanistic and functional studies. The results can uncover novel RNA dependent mechanisms associated with monocyte activation and dysfunction under diabetic conditions which will have a major positive impact and significantly advance the field. The completed studies could lead to the identification of much needed new biomarkers and therapies for diabetes induced accelerated inflammatory cardiovascular diseases.

Public Health Relevance

The escalating rates of diabetes and obesity have become major healthcare problems in the USA. This is compounded by the fact that they are associated with significantly accelerated rates of numerous debilitating and life-threatening complications like inflammatory cardiovascular and renal diseases. Although newer therapies are available for patients with diabetes, they are still succumbing to these complications at alarming rates. It is now believed that this could be due to a mix of genetics and the environment and that key genomic events and transcripts may mediate the complex interactions between the two. This Project will identify such novel new mechanisms by which uncontrollable inflammation and related complications can occur under diabetic conditions. The completed studies could lead to the identification of new biomarkers and novel drug targets for diabetic complications especially for patients who do not adequately respond to current therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-B (90))
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Jones, Teresa L Z
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City of Hope/Beckman Research Institute
United States
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Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55
Miao, Feng; Chen, Zhuo; Genuth, Saul et al. (2014) Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63:1748-62
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Kato, Mitsuo; Castro, Nancy E; Natarajan, Rama (2013) MicroRNAs: potential mediators and biomarkers of diabetic complications. Free Radic Biol Med 64:85-94
Leung, Amy; Natarajan, Rama (2013) Forgetting to switch off SMAD2 in aneurysmal disease. Circ Res 113:843-5
Leung, Amy; Trac, Candi; Jin, Wen et al. (2013) Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res 113:266-78
Miao, Feng; Chen, Zhuo; Zhang, Lingxiao et al. (2013) RNA-sequencing analysis of high glucose-treated monocytes reveals novel transcriptome signatures and associated epigenetic profiles. Physiol Genomics 45:287-99
Reddy, Marpadga A; Tak Park, Jung; Natarajan, Rama (2013) Epigenetic modifications in the pathogenesis of diabetic nephropathy. Semin Nephrol 33:341-53
Miao, Feng; Chen, Zhuo; Zhang, Lingxiao et al. (2012) Profiles of epigenetic histone post-translational modifications at type 1 diabetes susceptible genes. J Biol Chem 287:16335-45

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