Oxytocin-mediated calcium signaling in physiologic uterine contractility and uterine atony

Project summary Postpartum hemorrhage (PPH) is the leading global cause of maternal morbidity and mortality. Uterine atony, insufficient uterine contractility after placental delivery, causes 80% of PPH. Oxytocin is the medical standard of care for prophylaxis and first line treatment of PPH. However, the mechanism whereby oxytocin causes uterine contractility remains incompletely understood. There is a critical need to determine (1) how oxytocin causes uterine contractility, and (2) the cellular and molecular mechanisms that underlie compromised oxytocin response in uterine atony. Such knowledge is integral to the discovery of novel, targeted treatments for uterine atony. Recent data in mice highlight a role for the Transient Receptor Potential Vanilloid 4 (TRPV4) channel in oxytocin- mediated uterine contractility. To address human uterine contractility, Dr. Ansari proposes innovative translational research using uterine tissue and derived smooth muscle cell cultures from cohorts of parturients with normal contractility and uterine atony. She will uncover molecular and cellular mechanisms of human uterine contractility in normal physiology versus uterine atony, define the role of the TRPV4 channel, and explore whether pharmacologic activation of TRPV4 may represent a novel uterotonic strategy. The first aim centers on normal, physiologic contractility, and the second on the pathophysiology of uterine atony: Aim 1) Determine the functional relationship between oxytocin and TRPV4 and the mechanisms of TRPV4 activation in normal uterine contractility; and Aim 2) Define TRPV4-dependent and TRPV4-independent mechanisms underlying uterine atony through cellular and molecular assays including single nuclei RNA sequencing. Dr. Ansari’s training will be conducted under the experienced mentorship of Dr. David N. Cornfield (smooth muscle biology, calcium signaling, and single cell transcriptomics), and Dr. Virginia Winn (maternal fetal medicine, basic and translational research in obstetrics), in conjunction with expert advisors in TRPV channel biology, biobanking, uterine atony, and PPH. This training will be enhanced by the Chan Zuckerberg Biohub Physician Scientist Fellowship program, advanced coursework in translational medicine, single cell RNA sequencing, and research laboratory management, and the supportive infrastructure of Stanford’s Maternal- Fetal Medicine and Obstetric Anesthesia Divisions. Through this K23, Dr. Ansari will obtain broad-based knowledge and skills in laboratory research including advanced experiential training in uterine smooth muscle biology, calcium signaling, and single cell transcriptomics. These skills will equip her to pursue her long-term goal to develop an independent research career identifying new therapeutic targets for uterine atony at the bench with the ultimate goal of translating discoveries to clinical care to address PPH.