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

开发过程中的分化和分层：联合计算和实验研究

• 批准号: 1161621
• 负责人: Qing Nie
• 金额: $ 199.69万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1161621&HistoricalAwards=false
• 关键词: Differentiation; Stratification; during; Development; Joint

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.

上皮发育和再生涉及整合多种信号传导和转录活动的多层调节机制，以调节干细胞/祖细胞衍生的细胞谱系的动力学和空间分布。 在发育和再生过程中，像哺乳动物表皮这样的复层上皮是如何利用复杂的调控网络和细胞间的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约束的同时稳健地获得其期望的空间模式？研究人员使用系统生物学方法，结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，研究小组还描述和搜索了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，该项目开发了多尺度和随机模型，包括细胞内调控网络，细胞外形态发生，单个细胞，细胞分裂，细胞间通讯和组织生长。 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带来新的曙光，而且还将为其他上皮系统（如舌、食道、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共享分层组织、再生能力和组织极性。鉴于干/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，这是健康和医学的中心议题。 此外，研究人员将开展广泛的外展，教育和多样性活动，包括高中学生的细胞谱系建模夏季研究和一些具体活动，以加强代表性不足的本科生进入UCI跨学科博士学位的招聘。数学和计算生物学课程。整体研究和教育活动将涉及不同层次的学生，主题是连接研究和培训，为数学和生物学之间的跨学科培训和研究提供新的机会和更好的环境。