the first evidence that diabetic conditions in vitro and in vivo lead to inflammatory gene transcription in monocytes via novel nuclear chromatin remodeling and potential epigenetic mechanisms involving co-operative effects between transcription factors, coactivators and chromatin histone acetylation. We evaluated monocytes cultured in vitro with diabetic stimuli such as high glucose (HG) and ligands of advanced glycation end products (AGEs), as well as monocytes from diabetic patients. We have made excellent progress and completed most of our original Specific Aims and also initiated several new studies. This rapidly moving and dynamic field has opened several new avenues that will be investigated in this renewal. We have uncovered exciting new mechanisms of inflammatory gene expression in monocytes under diabetic conditions including the involvement of novel chromatin factors, and key microRNAs (mIRs) whose targets modulate chromatin remodeling as well as mRNA stability. The current renewal will thus take our studies to a new pioneering level and advance the field by unraveling hitherto unexplored mechanisms of regulation of genes associated with monocyte dysfunction in vitro and in vivo in diabetes. The hypothesis is that diabetic conditions lead to increased expression of inflammatory genes in monocyte /macrophages via transcriptional mechanisms involving chromatin histone modifications and miRs, as well as post-transcriptional mechanisms involving mRNA stabilization. This will be evaluated by 4 Specific Aims based on published and extensive new preliminary data.
Aims 1 and 2 will determine how diabetic conditions in vitro in cultured monocytes and in vivo in monocytes from diabetic subjects lead to the transcription of inflammatory genes via novel changes in the chromatin at these gene promoters.
Aim 3 will test the functional roles of two key new micro-RNAs (miRs) that are differentially regulated in diabetic monocytes /macrophages.
Aim 4 will examine new post-transcriptional mechanisms by which diabetic stimuli increase the stability of key inflammatory gene mRNAs via novel interplay between RNA binding proteins and miRs. Our state-of-the-art and innovative assessments of the cross-talk between the transcriptome, epigenome, ribo-gnome and the inflammasome can provide new insights into cellular events mediating monocyte dysfunction under diabetic and insulin resistant conditions. These completed studies can greatly advance our knowledge of diabetic vascular disease and uncover new therapeutic targets for the debilitating vascular complications of diabetes, Project Description Page 6
|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; 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|
|Reddy, Marpadga A; Natarajan, Rama (2016) Targeting miR-200c to Ameliorate Diabetes-Induced Endothelial Dysfunction. Diabetes 65:1152-4|
|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|
|Leung, Amy; Trac, Candi; Du, Juan et al. (2016) Persistent Chromatin Modifications Induced by High Fat Diet. J Biol Chem 291:10446-55|
|Bhatt, Kirti; Lanting, Linda L; Jia, Ye et al. (2016) Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy. J Am Soc Nephrol 27:2277-88|
|Leung, Amy; Stapleton, Kenneth; Natarajan, Rama (2016) Functional Long Non-coding RNAs in Vascular Smooth Muscle Cells. Curr Top Microbiol Immunol 394:127-41|
|Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55|
|Caramori, M Luiza; Kim, Youngki; Natarajan, Rama et al. (2015) Differential Response to High Glucose in Skin Fibroblasts of Monozygotic Twins Discordant for Type 1 Diabetes. J Clin Endocrinol Metab 100:E883-9|
|Schones, Dustin E; Leung, Amy; Natarajan, Rama (2015) Chromatin Modifications Associated With Diabetes and Obesity. Arterioscler Thromb Vasc Biol 35:1557-61|
Showing the most recent 10 out of 56 publications