Diabetes, obesity and insulin resistance (IR) are associated with chronic inflammation implicated in the development of numerous vascular complications, including atherosclerosis, which are the major causes of morbidity and mortality in the affected population. However traditional glycemic control and anti-inflammatory therapies have been quite ineffective in controlling the progression of complications, underscoring the need for more in-depth examination of underlying mechanisms. In the previous funding period, we made a major impact by demonstrating, for the first time, the involvement of epigenetics and long non-coding RNAs (lncRNAs) in promoting inflammation and cellular dysfunction in monocyte/macrophages under diabetic conditions. However, it is still unclear how these epigenetic layers can also inhibit endogenous protective factors leading to de- repression of inflammation in diabetes and obesity. Moreover, it is not clear how the epigenetic cross-talk between novel lncRNAs and enhancers regulate active versus repressed chromatin states to control the balance between inflammation and anti-inflammation, and if this cross-talk is disrupted in diabetes/obesity/IR. Studies in this renewal will address this critical gap in knowledge by establishing a novel role for protective lncRNAs acting via epigenetic mechanisms. This is supported by extensive new preliminary data, including the identification of two lncRNAs that are downregulated in monocytes (monos) from type 2 diabetic subjects, and in macrophages (macs) from obese mice. They have anti-inflammatory functions in monocytes/macrophages. Genes proximal to these lncRNAs with monos/mac-related functions, and overlapping enhancers, are also mis-regulated. We thus hypothesize that diabetes and obesity re-program the monos/mac transcriptome and epigenome to down-regulate key protective lncRNAs, and modulate related enhancers, resulting in upregulation of genes that promote monos/mac inflammation, activation and dysfunction. This will be tested via three Specific Aims:
Specific Aim 1 will determine the upstream mechanisms regulating the two newly identified anti-inflammatory lncRNAs, and the functional consequences of their downregulation by diabetic/IR stimuli.
Specific Aim 2 will define the downstream targets and epigenetic mechanisms of actions of these lncRNAs in regulating genes involved in monos/mac dysfunction under diabetic conditions.
Specific Aim 3 will determine the in vivo functions of candidate lncRNAs using mouse models of diabetic inflammatory vascular complications. This innovative study uses cutting-edge genomics, RNA targeting and translational approaches that can alter existing paradigms and have a positive impact by uncovering new lncRNA mediated epigenetic regulation of inflammation in diabetes. The outcomes can significantly advance our understanding of the dysregulated lncRNA-Ome in diabetic vascular complications with potentially far reaching clinical and therapeutic implications.

Public Health Relevance

The escalating rates of diabetes and obesity have become major healthcare problems in the USA, more so because these metabolic disorders are associated with significantly accelerated rates of life-threatening complications like inflammatory cardiovascular diseases. This Project will examine novel new mechanisms underlying uncontrollable inflammatory diabetic complications. The completed studies could lead to the identification of new biomarkers and 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 #
5R01DK065073-17
Application #
9720891
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Jones, Teresa L Z
Project Start
2003-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
17
Fiscal Year
2019
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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