Dissecting the Inflammation Resolution Mechanisms in Endometrial Health and Disease

Project Summary/Abstract: In the human endometrium, the acute patterns of immune infiltration and expression of inflammatory signals are found across the menstrual and are needed for maintaining reproductive function including implantation, menstruation and regeneration. Regulation of these timely events is primarily driven by fluctuations in estrogen and progesterone signaling, however, the regulatory mechanisms that govern resolution of these inflammatory signals remain unknown. The resolution of inflammation is a coordinated and bioactive process aimed at restoring tissue integrity and function after acute inflammatory insults. Poor resolution of inflammation is a mechanism in the pathogenesis of many chronic inflammatory diseases, like endometriosis. A central question in endometrial biology that remains unanswered is how the resolution of inflammatory processes is regulated across menstrual health. We will investigate the role of specialized pro-resolving mediators (SPMs), a class of lipid-derived molecules that act as potent endogenous immunoresolvents that orchestrate the resolution of inflammation and immune function, in menstrual health. We hypothesize that fluctuations in estrogen and progesterone regulate the inflammatory responses of the endometrium via SPM biosynthesis and dysregulation of SPM signaling drives the pathogenesis of endometriosis. One significant barrier to progress in this area is the lack of humanized models that can temporally and mechanistically parse the immune- endocrine interactions in human endometrial health. We deploy innovative multi-cellular organoid in vitro models and computational analysis of the human endometrium datasets to address three key knowledge gaps: 1) is the resolution of inflammation is regulated by sex hormones, 2) how do changes in inflammatory networks positive and negatively impact reproductive processes and 3) can these pathways be targeted as a non-hormonal treatment for endometriosis. In this line, we will use this framework to evaluate how extrinsic factors, like dietary- derived fatty acids impact subsequent inflammatory responses. A deeper understanding of the lipidome and the mediators that regulate the resolution of inflammation is necessary to advance our understanding of fundamental reproductive and inflammatory events. A primary goal for this proposal period is to deliver a comprehensive and mechanistic atlas of SPM signaling pathways in endometrial health to interrogate how inflammatory signals are impact reproductive function. In the end, we will gain fundamental insights into the sex hormone and immunological origins of reproductive function, setting the stage for understanding fundamental biological and inflammatory processes including menstrual bleeding, regeneration and nociceptive pain signaling. Ultimately, findings from this research program will open new avenues for using SPM as novel therapeutic target.