Wednesday, May 1, 2024
5/1/2024
PROJECT SUMMARY/ABSTRACT Organ shape is vital for proper function. Malformations in the looping and folding of the heart, for instance, represent the leading cause of birth defect mortality in humans. Visceral organs rely on the coordinated activity of multiple laminar tissue layers to fold and coil into targeted shapes. While the community has learned much about the genetic signals governing cell fates during development, less is understood about the mechanical stresses and tissue dynamics that translate gene expression into the shapes of organs. This proposal aims to link hox gene expression to physical forces driving 3D multilayer organ shape change using the D. melanogaster midgut as a model system. The midgut begins as a tube of two concentric tissue layers that undergoes a sequence of constrictions to fold into chambers. Hox genes — conserved master regulators of patterning during development — have long been known to govern the ¿nal shape of this organ, but the mechanical stresses and tissue dynamics translating hox expression into organ shape have remained elusive. We recently found that organ constrictions proceed through a mechanical program mediated by calcium pulses in the outer layer, under the control of hox genes. Advances in light-sheet microscopy now enable live visualization of the whole organ at sub-cellular resolution during development. Integrating these imaging methods with physics approaches provides the ability to follow cell dynamics across tissue layers throughout morphogenesis and quantitatively relate genetic patterning in the tissue to the tissue mechanics and dynamic cellular behaviors driving 3D shape change. The proposed work aims to ¿rst (1) decode the relationship between the hox gene expression pattern to the downstream pattern of calcium pulses in the midgut. (2) Secondly, a physical model will relate calcium pulses to tissue-scale mechanical stress, using spatiotemporal maps of calcium activity to constrain an in silico model of the morphing tissue. Together, these aims will reveal how genetic patterning controls a mechanical process to sculpt complex shapes in a bilayer organ. (3) Finally, this proposal will address how the midgut model visceral organ coils into a chiral tube later during development. Recent discoveries of `cell intrinsic' chirality, in which cytoskeletal machinery breaks left-right symmetry, have proven to provide a major role in determining organ-scale chirality. The mechanical process by which cell chirality translates into 3D organ-scale shape change, however, remains largely unknown. By combining the in toto imaging toolkit and molecular biology approaches mastered during the K99 phase with my expertise in chiral mechanics from my PhD, this aim will link cellular chirality to the dynamics of organ-scale coiling. Together, these research aims and the training in biology, microscopy, and modeling during the K99 phase will ensure I am equipped to begin an independent research lab revealing the physical mechanisms harnessed by biology to sculpt complex shapes of visceral organs.
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