Diabetes, insulin resistance and the metabolic syndrome are associated with significantly accelerated rates of cardiovascular disease. Abnormal activation of circulating monocytes triggered by inflammatory cytokines and chemokines has been implicated in this pathology but the underlying molecular mechanisms are not fully understood. In the previous funding period, we provided 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.
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