A multi-disciplinary approach to uncover novel insights of endocervical mucus secretion for future drug discovery

The goal of our work is to uncover the cells and pathways that affect mucus changes downstream of hormonal changes, with the long-term goal of using this information to inform the development of novel, non-hormonal therapeutics targeting the endocervix that would inhibit (contraception) or enhance fertility. Endocervical cells produce mucus, and changes in mucus consistency during the normal menstrual cycle influence human health and fertility. For natural fertility to occur, mucus must change from a highly viscous form that blocks sperm penetration to a highly fluid form that allows for sperm penetration and fertilization. Mucus also blocks entry of pathogens in the gravid and non-gravid uterus, playing a key role in overall health of the uterus and upper reproductive tract. Despite the known biological and clinical importance of the endocervix and mucus in fertility, contraceptive studies in the endocervix have been methodologically limited as clinical studies of the endocervix lack discriminating, biologically meaningful endpoints and laboratory studies are limited by availability of cellular and animal models. Meanwhile, research in the airway and other non-reproductive organs have made major advances in both understanding the physiology of mucus properties and development of research tools for investigating epithelial-mucus interactions. Airway studies have revealed that mucin glycoproteins and regulation of their hydration via epithelial ion channels underpin the biophysical and rheological properties of secreted mucus. Our study builds on our prior work establishing that the endocervical epithelia is similar to epithelia from other mucosal organs, including the mucin protein constituents, expression and function of ion channels, and testability of cellular mucus changes. Applying the most recent knowledge of epithelial mucus biology to cycle-dependent fluctuations of endocervical mucus characteristics leads us to hypothesize that female sex hormones estradiol and progesterone regulate mucus biophysical properties, mediated by alteration of epithelial cell populations and states, mucus protein composition, and ion channel transporter activities in the endocervix. To do this, we will leverage a unique multi-disciplinary, multi-institutional collaboration bringing together expertise in reproductive health and the endocervix, epithelial cell biology, mucus and mucin biophysical properties, ion channel biology, and next-generation sequencing studies and bioinformatics in the reproductive tract. We will combine 1) an established clinical trial model of steroid hormone ablation and replacement to collect endocervical cells and mucus under highly controlled hormonal conditions in humans with 2) a novel in vitro model of conditionally reprogrammed endocervical cells that leverages an array of phenotypic endpoints of mucus changes adapted from highly successful airway drug discovery programs. By combining clinical and in vitro studies, we expect to discover and validate novel mechanisms responsible for regulation of mucus biophysical properties during the menstrual cycle in the cervix and in turn provide a scientific basis for clinical implication of mucus as a tool to control fertility. Project Number: 5R01HD115770-02 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Leo Han | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $707,198 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R01HD11577002