Role of mechanical forces in cardiac s-looping

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DESCRIPTION (provided by applicant): Although the genetic and molecular mechanisms of heart development have received considerable attention, the biomechanical forces driving these complex shape changes have largely been ignored. The goal of this project is to make inroads into our understanding of embryonic heart development. Using a combined experimental and computational approach, the project will uncover the forces responsible for the remarkable shape changes that transform a simple straight tube into a four-chambered pump. The project will focus on a period of development termed "s-looping", when the primitive atrium, which initially lies inferior to the primitive ventricle, moves to its definitive position superior to the ventricle. The project has two specific aims: (1) Carefully characterize s-looping qualitatively and quantitatively via experiments. Then develop a computer model that includes internal loads, actin fiber orientations, and boundary conditions as determined by experiments. (2) Use the computer model developed in Aim 1 to determine the distribution of mechanical forces that drive early cardiac s-looping. The chick heart, whose development closely parallels that in humans, will be used as the experimental model. The finite element technique will be used to develop computer models. For the first aim, s-looping will first be characterized by measuring local morphogenetic stress and strain fields using fluorescent labeling and determining the local actin orientations by confocal microscopy. In addition, chemical perturbations will be used to determine possible roles for actin polymerization and cytoskeletal contraction - two actuators that are important in c-looping, which precedes s-looping. Also, mechanical perturbations will be used to investigate forces applied by the various constituent parts of the s-looping heart. For the second aim a computational model for s-looping will be constructed. Then, by comparing the experimental and model-predicted local (i.e., stress and strain fields, outcomes of mechanical perturbations) and global (i.e., gross shape, length, and diameter changes) outcomes, the force distributions responsible for s-looping will be determined. Relevance to Public Health According to data from the American Heart Association, 1,000,000 Americans have some form of congenital heart defect and 35,000 babies are born every year with some form of congenital heart disease. Abnormal looping is a primary reason for congenital heart disease. This project will shed light on the poorly-understood mechanics of looping. PUBLIC HEALTH RELEVANCE: Project Narrative According to data from the American Heart Association, 1,000,000 Americans have some form of congenital heart defect and 35,000 babies are born every year with some form of congenital heart disease. Abnormal looping is a primary reason for congenital heart disease. This project will shed light on the poorly-understood mechanics of looping. 1