Integrating at Sub-Cellular Level the Biochemical and Biomechanical Signals with Stochasticity to Study the Regulation of Tissue Growth

本研究的目的是了解生物化学信号和细胞力学如何相互协调，以调节组织生长，在发育过程中实现特定的形状和健壮的大小。生长调控仍然是发育生物学和再生医学的一个未解之谜和巨大挑战。不受控制的组织生长可能导致异常发育和致命疾病，包括癌症。数学模型为模拟生物系统和测试生长控制机制的假设提供了一个重要的新工具，目前仅靠实验很难或不可能。该项目将研究生长调节机制，包括那些难以用现有模型测试的机制，通过开发一个新的数学模型，结合生化信号和细胞力学特性，以及它们之间的相互作用。通过将该模型应用于经典生物系统，它将为生长控制的基本原理提供新的见解。加州大学河滨分校是一所拥有不同学生背景的西班牙裔服务机构。这项研究将吸引本科生和研究生参与跨学科项目，并将新兴成果纳入课程作业。外展活动，包括研讨会、讲习班和夏季研究项目，将与数学系、加州大学河滨分校生物学定量建模跨学科中心和南加州地区的社区学院协调。在组织发育过程中，细胞对化学和机械信号作出反应，协调生长和增殖，从而精确而稳健性地获得组织的整体形状和大小。果蝇翅盘是一种上皮原始器官，后来形成成年果蝇的翅膀，具有相对简单的几何形状，细胞数量有限，生长迅速，以及基于其他发育系统中保守分子的分子信号网络。研究这一经典的生物系统可以揭示潜在的一般生长调节机制，适用于其他发育系统。本跨学科研究的主要目标是在亚细胞水平上以机械的方式为翼盘组织建立一个耦合的力学化学模型。将考虑不同形态因子在正交方向上的作用以及细胞内基因调控网络。亚细胞力学性能将通过使用涉及不同细胞类型的先进亚细胞单元模型来考虑。细胞刚度、细胞-细胞粘附和生化信号之间的相互作用将包括在这个多尺度框架中。该模型将用于检验细胞生长速率由生化信号的时间变化决定的假设，以及由实验数据提出的通过分子线索和机械反馈实现均匀生长的假设。这种耦合模型将允许探索空间均匀生长和翼盘囊袋形状不对称的新机制，以及研究生物化学或/和生物力学信号的随机性对生长控制机制的影响。该项目由数学科学部数学生物学项目和分子与细胞生物科学部细胞动力学与功能项目联合资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The goal of this research is to understand how the biochemical signals and cell mechanics coordinate with each other to regulate tissue growth in achieving specific shape and robust size during the development. Growth regulation remains an unsolved mystery and a grand challenge for both developmental biology and regenerative medicine. Uncontrolled tissue growth can result in abnormal development and fatal diseases including cancer. Mathematical models offer an important new tool both to simulate biological systems and to test hypotheses in growth control mechanisms, currently difficult or impossible for experiments alone. This project will investigate mechanisms in growth regulation, including those that are difficult to test by using existing models, by developing a novel mathematical model incorporating biochemical signals and cell mechanical properties, as well as the interaction between them. By applying this model to a classical biological system, it will provide novel insights into the fundamental principles of growth control. UC Riverside is a Hispanic-serving institution with diverse student background. This research will engage undergraduate and graduate students in interdisciplinary projects and incorporate emerging results into coursework. Outreach activities, including seminars, workshops, and summer research programs, will be coordinated with department of mathematics, Interdisciplinary Center for Quantitative Modeling in Biology at UC Riverside, and community colleges in the area of southern California. Cells response to both chemical and mechanical signals to coordinate the growth and proliferation during the tissue development, such that the overall shape and tissue size can be obtained precisely with robustness. The Drosophila wing disc, an epithelial primordial organ that later forms the adult fruit fly wing, features a relatively simple geometry, limited number of cells, rapid growth, and a well understood molecular signaling network based on molecules conserved in other developmental systems. Studying this classical biological system can reveal underlying general mechanisms of growth regulation, applicable in other developmental systems. The main goal of this interdisciplinary research is to develop a coupled mechanochemical model at sub-cellular level in a mechanistic way for the wing disc tissue. Different morphogens acting in orthogonal directions as well as an intracellular gene regulatory network will be considered. Sub-cellular mechanical properties will be taken into account by using an advanced subcellular element model involving different cell types. The interaction between cell stiffness, cell-cell adhesion and biochemical signals will be included in this multiscale framework. This model will be applied to test the hypothesis that the rate of cell growth is determined by the temporal change in biochemical signals and the hypothesis that uniform growth is achieved by molecular cues and mechanical feedback, suggested by experimental data. This coupled model will allow exploration of the new mechanisms for spatially homogeneous growth and the asymmetric shape of the wing disc pouch, as well as investigation of the effects of stochasticity in biochemical or/and biomechanical signals on growth control mechanisms. This project is funded jointly by the Division of Mathematical Sciences Mathematical Biology Program and the Division of Molecular and Cellular Biosciences Cellular Dynamics and Function Program.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.