This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In the avian embryo, bilateral heart primordia fuse to form a tube at the midline. Subsequently, this tube undergoes a process of flexion and rotation; resulting in a looped heart. Our long-term goal is to determine if multiple genetic and signaling defects converge at a common mechanical nexus to prevent heart fusion - resulting in cardia bifida. It is known that local cell-extracellular matrix (ECM) interactions are critical for early heart development. In addition, we propose that global tissue deformations directly influence cell motion and the ongoing reorganization of the ECM necessary for proper heart tube fusion. Accordingly, the following hypotheses will be tested: First, that cells and ECM components required for heart morphogenesis are recruited from distant sites; Second, that these 'raw materials' are displaced by physical tissue-level events that are not dependent on autonomous cell motion; Third, that proper heart morphogenesis requires ongoing tissue-level reorganization of cell collectives and the 'recruited' ECM fibrils; and Fourth, that perturbations to the mechanical micro-environment, such as disruption of local tension fields or cell-ECM interactions, will cause reproducible heart malformations. Accordingly, we will: 1) Determine mesodermal cell and ECM fibril position-fate maps during avian bilateral heart tube fusion in normal and experimentally perturbed embryos; 2) Compute the component of total cell displacements attributable to autonomous motion versus tissue convection; 3) Compute strain in the heart-forming regions of normal and experimentally perturbed embryos; and 4) Construct a predictive finite element model encompassing tubular heart morphogenesis.
These aims will be accomplished using DIC and epifluorescence time lapse microscopy and subsequent computational analyses of the resulting image frames.
Computational imaging data will indicate the importance of mechanical patterning during heart morphogenesis. Predictive computer models will characterize the bio-mechanics of heart malformations and may provide information to help prevent related heart defects.
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