Regulation and function of multicellular calcium signaling in epithelial growth and regeneration

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ABSTRACT Many diseases including Alzheimer's, cardiac arrhythmias, and multiple metastatic cancers exhibit dysregulated intercellular Ca2+ transients (ICTs). Calcium ions (Ca2+) serve as critical second messengers involved in cell signaling and in coordinating proper organ development. Ca2+ is also important in the transduction of mechanical forces in tissues and for integrating multiple biochemical signals from diffusible proteins termed morphogens. Both morphogen signaling and mechanical force inputs have been implicated in the size control and patterning of developing organs. However, much is still unknown about the regulation and functions of ICTs during tissue growth and regeneration. For example, it has been known for some time that a left-right asymmetry in intracellular Ca2+ concentrations exists during vertebrate development; however, the exact mechanism governing this observed asymmetry remains unclear. The overall goal of the research program is to identify the underlying principles and mechanisms that govern the coordination of cellular processes during growth and regeneration with a particular emphasis on understanding the regulation and functions of ICTs. Our lab is at the forefront of developing multi-disciplinary approaches to define the interplay between ICTs, morphogen signaling, and mechanical forces during tissue growth and regeneration. We have recently discovered anterior-posterior patterning of ICTs in developing Drosophila (fruit fly) wing discs. We have identified that genetic disruption of the Hedgehog (Hh) pathway, which directs patterning of the anterior- posterior axis in the wing primordium, abolishes this observed asymmetry of ICTs. This establishes a fundamental link between morphogen signaling and ICTs in a developmental context. We are now currently focused on bridging the large gap between descriptive observations and systems-level quantitative analysis of ICTs. We are studying the impact of ICTs on morphogen signaling, organ development, and regeneration by modulating ICTs and morphogen activity both genetically and pharmacologically in Drosophila wing discs. Further, we are capturing dynamic and multi-scale measurements of ICTs to characterize modulators of Ca2+. We are also developing computational models to test hypothesized cross-talk between morphogenetic signaling and Ca2+ signaling dynamics. Cumulatively, this research will result in novel quantitative imaging approaches to map ICTs to morphogenetic patterning in developing and regenerating tissues. A mechanistic understanding of ICT regulation and function will lead to critical insights into how tissues grow and regenerate. This fundamental understanding also will allow us to understand and mitigate unwanted side effects of targeting Ca2+ signaling therapeutically and will potentially reveal innovative strategies for accelerating tissue regeneration.