Elastic energy storage and viscous dissipation driving buckling morphogenesis of the small intestine

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Trustees of Columbia University in the City of New York $149,190 on September 25, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate elastic energy storage and viscous dissipation mechanisms driving buckling morphogenesis of the small intestine.

The research examines how the small intestine forms its stereotyped looped morphology during embryonic development through differential growth between the elongating gut tube and the slowly elongating mesentery. Errors in looping morphogenesis cause congenital disorders including midgut volvulus and gastroschisis. The funded work investigates the role of the mechanoresponsive YAP protein in balancing elastic energy storage—which drives buckling—with energy dissipation through tension-mediated cell proliferation to confer stereotypy to looping morphogenesis, and examines post-buckling behaviors necessary to dissipate elastic energy once morphogenesis is complete.

Work is performed at Columbia University in New York, New York, with period of performance from September 25, 2026, through April 30, 2029. This is a Project Grant, a form of assistance that supports research activities at eligible academic and research institutions.

Abstract

The small intestine exhibits a stereotyped looped morphology to allow for ordered packing into the abdominal cavity and efficient nutrient absorption through increased surface area. Errors in looping morphogenesis during development are associated with devastating congenital disorders such as midgut volvulus and gastroschisis. Looping morphogenesis is attributed to differential growth between the rapidly elongating GUT tube and its attached mesentery, a thin membranous tissue anchoring the tube to the dorsal body wall. Elongation of the initially straight tube is resisted by the slowly elongating mesentery, producing tension in the mesentery and compression on the tube that buckles IT into regular loops. Work by the sponsor demonstrated that BMP signaling sets up differential growth by limiting elongation of the mesentery through changes in cell density - but not cell number. However, the mesentery does grow and cells do proliferate, providing a counterbalance to relieve mesenteric tension and ensure that the stereotyped target morphology is achieved. In other words, elastic energy storage in the mesentery, which drives looping, must be balanced with energy dissipation, yet the underlying pathways are unknown. More broadly, how energy storage and dissipation are coordinated during development is not well understood in most contexts. Working from strong preliminary data collected by the sponsor, aim 1 investigates the role of the mechanoresponsive YAP protein in balancing energy storage with dissipation through tension-mediated cell proliferation to confer stereotypy to looping morphogenesis. While storage of elastic energy is essential for buckling morphogenesis in the intestine and elsewhere in the embryo, IT is also necessary to dissipate that energy once morphogenesis is complete. However, such post-buckling behaviors have received less attention. Aim 2 builds on striking observations by the applicant that radial symmetry of the mature intestinal tube is broken at the end of looping by a depletion of ventral ECM, to test if bending strains generated during buckling drive mechano-responsive ECM remodeling to dissipate stored energy and stabilize buckled tissue morphology. Together, these aims will further our understanding of how organs utilize physical forces to guide form and to preserve IT once morphogenesis is complete. Through these aims, the applicant will receive cross-disciplinary training in a range of techniques including chick embryology, molecular and cell biology, microscopy, and biomechanics. The applicant will receive strong mentorship from the sponsor, CO-sponsor, and advisory committee, including technical and professional training, and career planning support. Important training activities include attending and presenting her findings in cross-department seminars and conferences, participation in writing and research ethics workshops, and mentoring other trainees, among other activities. In SUM, these experiences will prepare the applicant for postdoctoral research in academia studying regenerative medicine from a developmental biology standpoint.