COMPUTATIONAL MODELS OF MICRORNA-MEDIATED AND HIF-COORDINATED SYNTHESIS OF VEGF AND TSP-1: INSIGHTS INTO NOVEL THERAPEUTIC STRATEGIES IN CANCER AND PERIPHERAL ARTERIAL DISEASE

MicroRNAs are short, non-coding small RNA molecules that are found critical in the regulation of gene expression in a variety of human diseases. HRMs (hypoxia-responsive microRNAs) are a specific group of microRNAs that are regulated by hypoxia. Recent studies revealed that several HRMs including let-7 family microRNAs were highly induced in response to HIF (hypoxia-inducible factor) stabilization in hypoxia, and they potently participated in angiogenesis by targeting AGO1 (argonaute 1) and thereby indirectly regulating the downstream pro- and anti-angiogenic factors. Here we constructed two novel mass-action based computational models of microRNA control of HIF-coordinated VEGF (vascular endothelial growth factor) and TSP-1 (thrombospondin 1) synthesis, respectively, in endothelial cells to quantitatively investigate the roles of microRNAs, especially HRMs, in modulating the cellular adaptation to hypoxia. The model parameters were optimized and the simulations based on these parameters were validated against several published in vitro experimental data. To advance the mechanistic understanding of oxygen sensing in hypoxia, we demonstrated that the rate of HIF-1α nuclear import substantially influences its stabilization and the formation of HIF-1 transcription factor complex. We described the biological feedback loops involving let-7 and AGO1 in which the impacts of external perturbations were minimized; as a pair of master regulators when low oxygen tension was sensed, they coordinated the critical process of VEGF and TSP-1 desuppression in a controlled manner. We illustrated that a critical signaling axis responsible for TSP-1 repression in tumor involves the interactions between Myc proto-oncogene protein and let-7. Prompted by the model-motivated discoveries, we proposed and assessed novel pathway-specific therapeutics that modulate angiogenesis by adjusting VEGF/TSP-1 synthesis in tumor and ischemic cardiovascular disease. Through simulations that capture the complex interactions between miRNAs and miRNA-processing molecules, this model explores an innovative perspective about the distinctive yet integrated roles of different miRNAs in angiogenesis, and it will help future research to elucidate certain dysregulated miRNA and gene profiles found in cancer and various cardiovascular diseases