Calcium activated chloride channel modulation of myometrial excitability

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 DESCRIPTION (provided by applicant): Preterm birth is an enormous, growing global health care challenge. In the United States, >520,000 preterm births occur each year, many of which are associated with substantial morbidity. Although research has made insights into the mechanisms contributing to pre-term labor (PTL), the therapeutic armamentarium for PTL remains limited and inefficacious. However, the recent identification of the anoctamin (ANO) family of calcium-activated chloride channels has revolutionized our understanding of how these chloride channels play integral roles in modulating membrane potential, pacing, and contractility in other smooth muscle tissues. In this current proposal we establish ANO1's functional importance in the contractility and pacing frequency of human uterine smooth muscle (USM), determine the feasibility of using ANO1 as a therapeutic target to attenuate human USM contractions in vitro, and explore the underlying molecular mechanisms responsible for these beneficial effects. In particular, studies will span whole tissue functional organ bath experiments on fresh human myometrium strips harvested from late gestation c-section patients to mechanistic cell based studies focusing on the role of these channels on driving USM cell membrane potential, in calcium handling and filamentous-actin dynamics. We will employ a wide range of techniques including confocal microscopy, electrophysiology, in vivo and in vitro gene editing, and pharmacological antagonist strategies to establish the role of this channel family in human uterine contractility. The work is purposed to not only establish the importance of this channel in normal uterine smooth muscle physiology, but to also ascertain if it may serve as a new target to treat pre-mature contractions. As such, the potential for a highly translational therapy for pre- term labor exists.