Tissue morphogenesis: A study of molecular machines and cell mechanics

描述（由申请人提供）：该资助寻求对组织形态的生物物理学理解：我们如何解释细胞组织的特征形状和组织水平？遗传学和细胞生物学已经获得了许多关于调控形态的重要生物分子的信息。然而，亚细胞（nm）尺度上的分子活性与组织（mm）尺度上的形态之间的联系尚未得到证实。为了建立这样的联系，该基金利用了一个跨学科研究团队的能力，将理查德·卡尔休（西北大学）小组的细胞生物学和遗传专业知识与萨沙·希尔根菲尔特（伊利诺伊大学）小组在软材料物理学和理论力学方面的专业知识结合起来。该项目的主要目标是上皮组织力学的数学建模。在发表的结果中，研究小组发现果蝇眼上皮细胞采用的形状和相邻关系实现了被动能量最小化。沿着细胞膜平面的力变得平衡，导致机械平衡。重要的作用力是细胞间黏附和肌动蛋白皮质收缩。我们提出，力的不平衡自然地导致了一个移动的组织系统，其中细胞接触和形状的变化导致组织达到局部能量最小的停滞状态。我们的目标是通过在某些细胞中设计力不平衡并描述静态最终结果来验证这一假设。如果正确，

DESCRIPTION (provided by applicant): This grant seeks a biophysical understanding of tissue morphology: how do we explain the characteristic shapes and levels of organization of cellular tissues? Genetics and cell biology have obtained much information about the biomolecules that are important in regulating morphology. However, the link between molecular activities on the subcellular (nm) scale and morphology on the tissue scale (mm) has not been made. To establish such a connection, the grant draws on the abilities of an interdisciplinary research team, combining the cell biology and genetic expertise of the group of Richard Carthew (Northwestern University) with expertise in the physics and theoretical mechanics of soft materials from Sascha Hilgenfeldt's group (University of Illinois). The main objective of the project is the mathematical modeling of epithelial tissue mechanics. In published results, the team found cells in the Drosophila eye epithelium adopt shapes and neighbor relations that achieve passive energy minimization. Forces along the plane of cell membranes become balanced, leading to a mechanical equilibrium. Important contributing forces are those due to intercellular adhesion and actin cortical contraction. We propose that force imbalances naturally lead to a moving tissue system in which the changes in cell contacts and shapes result in the tissue reaching stasis with a local energy minimum. We aim to test this hypothesis by engineering force imbalances in certain cells and describing the static end-result. If correct, the mathematical model will accurately predict the mechanical outcomes of such experiments. Extending the hypothesis further, one might consider that morphogenesis is a progressive series of local energy minima reached in response to force change. We aim to test this hypothesis with a mathematical model that describes a very defined mechanical pathway in the eye, where four cells change contact with each other. Will the model predict the mechanical features and ways in which adhesive and contractive forces change over time and location? Lastly, we know that other forces exist within tissues but do not understand their relative contributions to tissue mechanics. To achieve this, we will develop a mathematical model that also considers cellular viscoelasticity, fluid pressure, matrix adhesion, and organelle displacement. The model will assume that these forces balance in three dimensions, leading to a passive energy minimization. Understanding the biophysical nature of tissue morphology will have great benefit for regenerative medicine and tissue engineering.