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

上皮细胞的发育和再生涉及多层调控机制，整合多种信号和转录活动来调节干细胞/祖细胞衍生细胞系的动态和空间分布。在发育和再生过程中，像哺乳动物表皮这样的分层上皮是如何利用复杂的调节网络和细胞间通讯来控制其生长和细胞层的分层的？表皮系统如何在满足许多生物学限制的情况下获得理想的空间格局？研究人员使用系统生物学方法整合建模和实验来研究这些问题。除了确定新的关键调控回路并确定其在发育中的表皮中的特定功能外，研究小组还描述并寻找有关不同调控回路和模块在发育过程中增殖、分化和空间组织的能力、限制和权衡的一般原则。在计算方面，该项目开发了包含细胞内调节网络、细胞外形态因子、单个细胞、细胞分裂、细胞间通信和组织生长的多尺度和随机模型。这项研究的结果将为高性能计算带来新的计算算法和建模技术。这项工作不仅将为皮肤研究提供新的思路，而且还将为其他上皮系统（如舌、食管、胃和嗅觉上皮）建立一个基础范例，所有这些上皮系统都与皮肤表皮具有分层组织、再生能力和组织极性。鉴于干细胞/祖细胞在再生和肿瘤发生中的重要性，我们的研究也将对上皮组织工程和癌症治疗产生重要影响，这些都是健康和医学的中心话题。此外，研究人员将开展广泛的推广、教育和多样性活动，包括为高中生进行细胞谱系建模的暑期研究，以及为加强UCI数学和计算生物学跨学科博士项目招募代表性不足的本科生的几项具体活动。整体的研究和教育活动将涉及几个层次的学生，其主题是桥接研究和训练，为数学和生物学之间的界面的跨学科训练和研究提供新的机会和更好的环境。

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.