Differentiation and Stratification during Development: A Joint Computational and Experimental Investigation

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Epithelial development and regeneration involve multi-tiered regulatory mechanisms integrating multiple signaling and transcriptional activities to regulate the dynamics and spatial distributions of stem/progenitor cell-derived cell lineages. How does a stratified epithelium like the mammalian epidermis utilize complex regulatory networks and cell-to-cell communication to control its growth and stratification of cell layers during development and regeneration? How does the epidermal system robustly obtain its desirable spatial pattern while satisfying many biological constraints? The investigators use a systems biology approach integrating modeling and experimentation to study these questions. In addition to identifying new critical regulatory circuits and determining their specific functions in the developing epidermis, the research team characterizes and searches for generic principles on capabilities, limitations, and tradeoffs of different regulatory circuits and modules for proliferation, differentiation, and spatial organization during development. Computationally, the project develops multi-scale and stochastic models incorporating intracellular regulatory networks, extracellular morphogens, individual cells, cell division, cell-to-cell communication, and tissue growth. The outcome of the study will lead to new computational algorithms and modeling techniques for high-performance computing.This work will not only shed new light into skin research, but also establish a founding paradigm for other epithelial systems such as the tongue, esophagus, stomach, and the olfactory epithelium, all of which share with the skin epidermis a stratified organization, ability to regenerate, and tissue polarity. Given the importance of stem/progenitor cells in regeneration and tumorigenesis, our study will also have important implications on epithelial tissue engineering and cancer therapy, which are central topics in health and medicine. Furthermore, the investigators will conduct a broad range of activities on outreach, education and diversity, including summer research for high school students on cell lineage modeling and several specific activities for enhancing recruitment of underrepresented undergraduate students into the UCI interdisciplinary Ph.D. program on Mathematical and Computational Biology. The overall research and educational activities will involve students at several levels with a theme on bridging research and training to provide new opportunities and better environment for interdisciplinary training and research at the interface between mathematics and biology.