Endometriosis, Adenomyosis, and Infertility
Systems Biology and Tissue Engineering
Complex diseases like endometriosis and adenomyosis are very challenging to dissect with genetic studies [Ref 1]. 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 ( Fig 1). Our 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 (Fig 2) 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 [3-4], and found that that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct endometrial cell motility (Fig 3) 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.
We are developing a secure, portable software application to aid clinical management of endometriosis patients both pre- and post-surgically, and to collect more highly stratified information about patient symptoms and surgical findings.
Surgical Tools and Instrumentation For Diagnostics and Treatment
While the ultimate minimally invasive therapy for female reproductive diseases is non-surgical, we currently use surgical techniques to diagnose and treat several benign conditions such as endometriosis and uterine fibroids. Through the CGR network, we are currently developing novel therapeutic surgical tools to treat diseases with in the uterine and peritoneal cavity in the most minimally invasive technique possible [1-3].
Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of pre-term birth. The dense and protective mucus plug in the cervical canal is the primary barrier to microbial ascension. We developed a facile means to measure mucus “spinnbarkeit”, the complex non-Newtonian rheological properties of mucus and used this approach to show a robust relationship between spinnbarkeit and pre-term birth (Fig 4) . Ongoing studies focus on clinical translation of these observations into prospective studies for prediction of preterm birth risk, and development of mucus-modulating therapies for a range of reproductive disorders.
HIV and sexually transmitted diseases
One are of study is why susceptibility of HIV infection in women is increased in association with immune/inflammatory system responses to other pathogens present. Samples from clinical patients in South Africa are analyzed with respect to cellular and molecular components, using computational systems biology methods, to elucidate how resistance to HIV is compromised in women suffering from these co-morbid infectious diseases. Another area of study is how infectious agents are transported across mucus barriers and how mucins act as antiviral agents [1-3], for example by binding to sperm (Fig 5, from ).
Resources for Investigators
The CGR maintains a primary cell bank of endometrial cells from patients and controls and routinely collects primary tissue for in vitro studies of normal and diseased cell behavior. The CGR researchers have developed new protocols for collection of peritoneal fluid for detailed molecular analysis and train other research teams in these protocols, which augment other published standard protocols. The CGR has a Luminex immunobead facility for multiplex analysis of cytokines and other biomolecules. The CGR core lab routinely carries out live cell imaging assays and quantitative cell migration studies and shared protocols and approaches.