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化信号和细胞力学如何相互协调，以调节组织生长，以实现特定的形状和强壮的大小在发育过程中。生长调控仍然是一个未解之谜，也是发育生物学和再生医学面临的重大挑战。不受控制的组织生长可能导致异常发育和包括癌症在内的致命疾病。数学模型提供了一种重要的新工具，既可以模拟生物系统，也可以检验生长控制机制中的假设，目前仅靠实验是困难或不可能的。该项目将通过开发一种新的数学模型，结合生化信号和细胞机械特性，以及它们之间的相互作用，来研究生长调控的机制，包括那些用现有模型难以检验的机制。通过将这个模型应用于一个经典的生物系统，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服务于拉美裔美国人的机构，学生背景多样。这项研究将使本科生和研究生参与跨学科项目，并将新兴成果纳入课程工作。外展活动，包括研讨会、研讨会和暑期研究项目，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大学进行协调。细胞对化学信号和机械信号做出反应，协调组织发育过程中的生长和增殖，从而可以准确地获得整体形状和组织大小，并具有鲁棒性。果蝇的翼盘是一种上皮性的原始器官，后来形成了成年果蝇的翅膀，其特征是相对简单的几何结构，有限的细胞数量，快速的生长，以及基于其他发育系统中保守的分子的众所周知的分子信号网络。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。这项跨学科研究的主要目标是以力学的方式在亚细胞水平上建立翼盘组织的力-化学耦合模型。不同的形态原作用于不同的方向，以及细胞内的基因调控网络将被考虑。将通过使用涉及不同细胞类型的先进的亚细胞单元模型来考虑亚细胞的力学特性。细胞刚性、细胞间黏附和生化信号之间的相互作用将被包括在这个多尺度框架中。该模型将被用来检验细胞生长速度由生化信号的时间变化决定的假说和实验数据所提出的通过分子线索和机械反馈实现均匀生长的假说。这一耦合模型将允许探索空间均匀生长的新机制和翼盘袋的不对称形状，以及研究生化或/和生物力学信号中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部和分子和细胞生物科学部细胞动力学和功能程序部共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.