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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
4R01DK065073-14
Application #
9068878
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jones, Teresa L Z
Project Start
2003-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Das, Sadhan; Reddy, Marpadga A; Senapati, Parijat et al. (2018) Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms. Arterioscler Thromb Vasc Biol 38:1806-1820
Das, Sadhan; Zhang, Erli; Senapati, Parijat et al. (2018) A Novel Angiotensin II-Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells. Circ Res 123:1298-1312
Leung, Amy; Amaram, Vishnu; Natarajan, Rama (2018) Linking diabetic vascular complications with LncRNAs. Vascul Pharmacol :
Das, Sadhan; Senapati, Parijat; Chen, Zhuo et al. (2017) Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. Nat Commun 8:1467
Reddy, Marpadga A; Das, Sadhan; Zhuo, Chen et al. (2016) Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504. Arterioscler Thromb Vasc Biol 36:864-73
Kato, Mitsuo; Wang, Mei; Chen, Zhuo et al. (2016) An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun 7:12864
Grassi, Michael A; Rao, Vidhya R; Chen, Siquan et al. (2016) Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose. PLoS One 11:e0160504
Chen, Zhuo; Miao, Feng; Paterson, Andrew D et al. (2016) Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci U S A 113:E3002-11
Yuan, Hang; Reddy, Marpadga A; Deshpande, Supriya et al. (2016) Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15-Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy. Antioxid Redox Signal 24:361-75
Bhatt, Kirti; Kato, Mitsuo; Natarajan, Rama (2016) Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 310:F109-18

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