Thursday, April 3, 2025
4/3/2025
Regulation and function of multicellular calcium signaling in organ growth and regeneration - ABSTRACT Our research team seeks to elucidate the fundamental principles that govern cell communication during organ development with a long-term goal of programming cellular health and function to correct disease phenotypes. Organ size, shape, and function emerge from cell-cell interactions between heterogeneous cell types. Calcium ions (Ca2+) are essential second messengers that help coordinate each cell’s response to various interactions and stimuli. Impaired Ca2+ signaling in cells occurs in many skin diseases, Alzheimer’s, and metastatic cancer. However, much remains unknown about the functions of the spatiotemporal dynamics of Ca2+ signals in developing or regenerating organs. Our previous results have led to significant progress in answering critical questions of fundamental significance that also generate new goals for the next five years: 1. What regulatory principles govern the multicellular dynamics of Ca2+ signaling? Progress: We have mapped the signatures of Ca2+ signaling dynamics in a developing organ system, the fly wing imaginal disc, to test the hypothesis that the dynamics of Ca2+ signaling fine-tune organ size and serve as a readout of organ growth rate. Next-step Goal: How can we control organ growth, morphogenesis, or organ function by programming Ca2+ signaling dynamics? Knowledge gained from our previous research is now leading to techniques to reprogram cell physiology and function by manipulating Ca2+ signaling, enabling future applications in modeling human diseases. 2. What are the functional roles of Ca2+ signaling in regulating tissue formation and homeostasis? Progress: Ca2+ signaling ensures robust wound healing and regeneration, but we lack knowledge of how this occurs at the multicellular scale. Our computational studies provide a framework for decoding the contributions of Ca2+ signaling during tissue formation and homeostasis. Next-step Goal: How do Ca2+ dynamics drive mechanical feedback between tissues during development? Our research team will test how Ca2+ signaling regulates the proteins that drive tissue mechanics during morphogenesis with a focus on wing disc eversion. 3. Can high-content analysis of perturbations to the extended Ca2+ signaling toolkit identify new regulators of organ development? Progress: We have created high-content imaging methods to identify functional relationships between genes that regulate Ca2+ signaling and corresponding cell- and organ-level phenotypes. This imaging pipeline, combined with machine learning techniques, helped to answer many questions, including predicting mechanisms by which a new drug will act. These previous efforts have led to the identification of new hypothesized mechanisms and expansion of research goals that require new experiments, quantitative tools, and approaches. Next- step Goal: How does multicellular Ca2+ signaling mediate and contribute to endocrine-based inter-organ signaling development? This effort will lead to a whole-organ, systems perspective of how multicellular tissues coordinate physiological responses within the whole-organism context and will provide insights into critical mechanisms impacting congenital disabilities, tissue degeneration, and aging.
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