Discovery and therapeutic targeting non-coding RNAs in T1D- or T2D-associated atherosclerosis - Despite current therapies and prevention measures, individuals with type 1 diabetes (T1D) experience a disproportionately higher risk of cardiovascular events due to a more severe and accelerated atherosclerotic burden present in vessels, a longer duration of diabetes exposure, and often asymptomatic early disease that can lead to sudden cardiac death as the first manifestation of disease compared to patients with type 2 diabetes (T2D) or those without diabetes. Moreover, established lesions in the presence of T1D are more resistant to therapeutic strategies (diet or pharmacologic lipid-lowering) that normally facilitate plaque regression. Therefore, there is an urgent need for novel therapies to reduce the development of T1D- associated atherosclerosis that can lead to cardiovascular sequelae. Current paradigms suggest that chronic inflammation coupled with sustained endothelial inflammatory responses, altered macrophage chemotactic and efferocytotic functions, and accumulation of senescent cells may be critical links to the accelerated lesion progression and impaired regression with T1D. Therefore, targeting these processes in the vessel wall may provide a novel therapeutic approach to limit atherosclerotic progression and facilitate regression. However, significant gaps remain in the molecular underpinnings that regulate T1D-associated atherosclerotic pathobiology with limited studies derived from human coronary arteries. A large portion of the non-coding genome is actively transcribed and constitute microRNAs (miRNAs) or long non-coding RNAs (lncRNAs). Studies from our laboratory have uncovered novel cell-specific roles for a range of miRNAs and lncRNAs in regulating key endothelial cell-leukocyte inflammatory networks in atherosclerosis, such as NF-kB signaling. Considerable gaps exist though in our understanding of how human ncRNAs contribute to accelerated atherosclerosis and differences in T1D and T2D. We hypothesize the existence of evolutionarily conserved driver ncRNAs and their targets in the arteries of subjects with T1D and T2D and seek to uncover their expression, function, mechanism, and interactomes in the Cardiovascular Repository-T1D (CaRe-T1D) using unique approaches across humans, pigs, and mice. To better understand these ncRNAs we propose to: 1) identify and prioritize ncRNA expression from human subjects with T1D- or T2D-associated atherosclerotic lesions; 2) explore the functional significance and mechanistic targets of ncRNAs on cellular inflammation, senescence, and metabolic pathways; and 3) determine the therapeutic impact of altered ncRNA expression in the progression and regression of experimental T1D- or T2D-associated atherosclerosis models. The outstanding qualifications of our multi-disciplinary team in the ncRNA field, vascular biology, bioinformatics and transcriptomics, molecular imaging, and translational aspects of diabetes-associated atherosclerosis uniquely position us to establish an unprecedented molecular view of ncRNAs in the development of T1D-associated atherosclerosis that can inform new paradigms of RNA-based therapeutics for this devasting disease.
