Systems Biology and Tissue Engineering

Complex diseases like endometriosis and adenomyosis are very challenging to dissect with genetic studies. Protein activity states – for example, the activities of intracellular kinases and extracellular proteases – integrate dynamic information from genes through protein expression levels in response to extracellular cues and are feasible therapeutic targets. Research focuses on understanding how cell communication networks within and between cells are disrupted in disease, using a compendium of computational and experimental approaches that often involve highly multiplexed measurements. For example, by measuring the concentration of 50 different cytokines in the peritoneal fluid of endometriosis patients and analyzing the data in a multivariate way, we found a macrophage-driven immune network in a subset of patients and identified an intracellular kinase pathway controlling secretion of inflammatory cytokines. We are now applying these approaches to parse immune networks in infertility. Endometriosis and adenomyosis are also invasive diseases driven in part by growth factors shed proteolytically from the cell surface. We developed a new combined experimental and computational approach to analyze a compendium of protease activities in the context of endometrial cell migration, and found that that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct endometrial cell motility and that growth-factor-driven ADAM-10 activity and MET shedding are jointly dysregulated in the peritoneal fluid of endometriosis patients. To complement these systems biology studies on patient samples, we are building in vitro models of endometrium using synthetic biomaterials microenvironments that drive epithelial polarization in the context of a supporting stroma.