Current research spans a wide range of objectives whose diversity includes the understanding of global epidemiology and the detailing of molecular interactions leading to specific pathologies. This work aligns more closely with the goal of mechanistic clarity by elucidating several aspects of signaling pathways involved in inflammatory and obstetric pathologies. Prior research has confirmed the role of Receptors for Advanced Glycation End-Products (RAGE) activation in signaling leading to chronic inflammation such as that observed in chronic obstructive pulmonary disease (COPD). RAGE activation has also been identified in other disease states including diabetes, Alzheimer’s disease, osteoarthritis, and cancers. We examined the role of RAGE in the obstetric complication intrauterine growth restriction (IUGR) wherein fetal development is delayed and infants are born at low birthweight. Exposure to tobacco smoke is known to activate RAGE, and smoke exposure also increases risk for IUGR. We confirm a role for RAGE signaling in development of IUGR. RAGE inhibition by semi-synthetic glycosaminoglycan ethers (SAGEs) significantly improved fetal and placental weights and reduced inflammatory signaling molecules. Interactions between RAGE and other signaling pathways have been noted in several research endeavors, and we sought to further understand signaling interactions specifically in obstetric pathologies by examining relationships between RAGE and Gas6/AXL signaling. We confirm that RAGE and Gas6/AXL signaling are not independent. Using tobacco smoke as a means of inducing RAGE, we determined that total AXL is inhibited when RAGE is active, but that phosphorylated AXL is increased. Inhibition of RAGE also increased Gas6 expression. These interactions require further clarification, but provide a foundation to expand upon. We further studied interactions within the Gas6/AXL pathway independent of RAGE. High levels of Gas6 have been noted in the serum of some women with preeclampsia, and early diagnosis and treatment of preeclampsia are currently limited. We demonstrate that, in a rat model, administration of Gas6 during pregnancy is sufficient to induce symptoms of preeclampsia including high blood pressure, increased proteinuria, and decreased trophoblast invasion. This provides a novel model which will further both diagnosis and treatment of preeclampsia. We also demonstrated that trophoblast invasion is influenced in a cell-type dependent manner by Gas6 and mTOR signaling, with decreased trophoblast invasion when Gas6 is high in trophoblast cells, but increased invasion with high Gas6 in a pulmonary adenocarcinoma cell type and in oral squamous cell carcinoma cells. Our work has clarified details of both RAGE and Gas6/AXL signaling that are crucial to further study of the pathways in which they are active, and the pathologies resulting from signaling misregulation.
College and Department
BYU ScholarsArchive Citation
Hirschi Budge, Kelsey May, "RAGE and Gas6/Axl Signaling in Obstetric Complications" (2020). Theses and Dissertations. 8409.
RAGE, Gas6, AXL, inflammation, intrauterine growth restriction, preeclampsia