Our central hypothesis is that diabetic stimuli such as high glucose (HG) and advanced glycation end products (AGEs) induce inflammatory chemokines and cytokines in VSMC via novel in vivo nuclear chromatin remodeling mechanisms. These factors can induce vascular inflammation, VSMC-monocyte interactions and phenotypic changes and thereby lead to accelerated cardiovascular disease.
Specific Aim 1 is to examine the nuclear transcriptomic mechanisms by which diabetic stimuli lead to chemotactic gene expression in VSMC. Here we will determine the nuclear interplay between NF-kB transcription factor and key chromatin factors using gain- and loss-of-function approaches.
Specific Aim 2 is to evaluate the in vivo relevance of these nuclear mechanisms and factors in VSMC and aortas derived from mouse models of diabetes. Here we will determine the potential association with hyperglycemic memory, sustained gene expression and activation observed in these diabetic cells.
Specific Aims 3 and 4 are to determine the functional impact of diabetic and atherosclerotic conditions, and these chromatin changes in leading to vascular dysfunction by promoting heterotypic interactions between VSMC and monocytes in vitro and in the aortas of mouse models. Our preliminary results have uncovered novel hitherto unexplored vascular mechanisms of action of diabetic stimuli. Our state-of-the-art transcriptomic approaches in this proposal could significantly advance the field and make a key impact by unraveling new factors and mechanisms underlying the sustained vascular complications of diabetes. The completed results could provide strategies for the development of sorely needed newer and novel therapies to reduce the morbidity and mortality of diabetic cardiovascular disease. Project Description Page 6
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|Du, Juan; Leung, Amy; Trac, Candi et al. (2016) Chromatin variation associated with liver metabolism is mediated by transposable elements. Epigenetics Chromatin 9:28|
|Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55|
|Leung, Amy; Parks, Brian W; Du, Juan et al. (2014) Open chromatin profiling in mice livers reveals unique chromatin variations induced by high fat diet. J Biol Chem 289:23557-67|
|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|
|Leung, Amy; Natarajan, Rama (2013) Forgetting to switch off SMAD2 in aneurysmal disease. Circ Res 113:843-5|
|Jin, Wen; Reddy, Marpadga A; Chen, Zhuo et al. (2012) Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells. J Biol Chem 287:15672-83|
|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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