We are a basic science and translational research group studying the molecular mechanisms of pulmonary vascular disease and pulmonary hypertension (PH) – an example of an enigmatic disease where reductionistic studies have primarily focused on end-stage molecular effectors. To capitalize on the emerging discipline of “network medicine,” our research utilizes a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodent and human subjects to accelerate systems-wide discovery in PH. Our published findings were among the first to identify the systems-level functions of microRNAs (miRNAs), which are small, non-coding RNAs that negatively regulate gene expression, as a root cause of PH. Our lab developed novel in silico approaches to analyze gene network architecture coupled with in vivo experimentation. The results now offer methods to identify persons at-risk for PH and develop therapeutic RNA targets. This work is the cornerstone of our evolving applications of network theory to the discovery of RNA-based origins of human diseases, in general.
Defining the network biology of non-coding RNAs in pulmonary hypertension. To capitalize on the emerging discipline of “network medicine,” our research has recently utilized a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodent and human subjects to accelerate systems-wide discovery in PH. In doing so, our published work has been among the first to identify the crucial importance of microRNAs (miRNAs) in processes critical to PH progression. We have focused on the prediction and confirmation of how the PH gene network is globally controlled by miRNAs and other non-coding RNAs (i.e., lncRNAs), thus impacting vascular phenotypes in rodents and humans in vivo. With such a foundation, we aim to prove that combining network theory with experimental validation can accelerate systems-wide discovery and therapeutic strategy, by identifying novel disease genes, their roles within interconnected molecular processes, and the comprehensive response of those connections to pharmacologic interventions.
Studying the molecular regulation of mitochondrial metabolism by microRNAs. We have a keen interest in identifying mechanisms by which microRNAs control mitochondrial metabolism in hypoxia and in hypoxia-relevant diseases such as pulmonary hypertension (PH). Specifically, we identified the hypoxia-dependent microRNA, miR-210, as a regulator of the ISCU gene and thus essential for iron-sulfur biogenesis. Under acute hypoxia, such activity facilitates the shift of oxidative mitochondrial phosphorylation to glycolysis. Thus, our findings provided a fundamental understanding of the so-called “Pasteur” effect which improves cellular survival during hypoxic injury. We have extended these observations to prove that the miR-210-ISCU axis controls the metabolic dysregulation in PH pathogenesis in both human and rodent examples of disease. Importantly, we have also identified a new human cohort of patients carrying genetic mutations of ISCU who suffer from exercise-induced PH. Together, these findings establish iron-sulfur deficiency as a powerful and novel metabolic origin of PH, a new therapeutic target for PH, and perhaps, a foundation for discovery in other diseases that share similar pathogenic and metabolic underpinnings.
Defining the regulation of circulating microRNAs in hypoxia and exercise. We have been studying the biology of extracellular miRNAs in hypoxia and exercise. We were the first to establish a specific mechanism by which the Argonaute 2 protein can coordinate release and activity of miRNAs such as miR-210 under hypoxic stress. In translational studies, we were also the first to report the specific and dynamic regulation of plasma-based circulating miRNAs in states of acute and endurance exercise. Together, these findings suggest the biologic importance of circulating miRNAs in hypoxia and exercise and set the stage for greater in-depth analysis of the functions of these versatile molecules.