Smooth Muscle Mechanotransduction: Calcium Dynamics in the Developing Gut

PROJECT SUMMARY/ABSTRACT This NIH Mentored Clinician Scientist Development (K08) proposal describes a comprehensive 5- year training plan designed to establish Geoanna Bautista, M.D. as an independent physician- scientist focused on mechanosensitive signaling pathways that contribute to neonatal intestinal dysmotility. Prematurity is the leading cause of death and disability in infants in the United States, and intestinal dysmotility resulting from an immature GI system is a significant yet understudied complication. Yet, no effective therapies address prematurity-related intestinal dysmotility due to critical knowledge gaps in understanding the development of GI motility. To address this foundational gap, Dr. Bautista will investigate mechanosensitive regulation driving intestinal maturation, which is important for establishing normal GI motility. Based on strong preliminary data supporting a critical role of the mechanosensitive ion channel, Piezo1, in normal intestinal motility and development, Dr. Bautista will test the hypothesis that Piezo1 is developmentally regulated and has a distinct role in the modulation of SMC Ca2+ activity during intestinal maturation. She will employ her previously established conditional knockout murine model to selectively deplete Piezo1 in SMCs during the neonatal period, combined with cutting-edge techniques such as super-resolution microscopy, live single cell and in situ Ca2+ imaging with and without stretch, to rigorously test this hypothesis. Specifically, in Aim 1, she will define the precise distribution and role of Piezo1 activation in SMCs of the developing intestine, and in Aim 2, she will determine the developmental consequences of Piezo1-deficient SMCs for intestinal contractility. The data to be obtained will provide new knowledge and mechanistic insights into the mechanical regulation of SMC [Ca2+]i signaling during intestinal development. More importantly, Dr. Bautista will gain training from the pioneering expertise of her diverse mentorship team in an excellent scientific environment. Dr. Bautista’s long term goals are to: 1) lead and perform rigorous mechanistic research to test clinically relevant models of intestinal mechanobiology during gut development, and 2) utilize these findings to explore innovative therapeutic strategies to address the burden of intestinal dysmotility in neonates. These goals will form the foundation of her independent research program, aligning closely with the NIDDK’s strategic plan and overall mission.