Tissue morphogenesis: A study of molecular machines and cell mechanics

组织形态发生：分子机器和细胞力学的研究

• 批准号: 8471590
• 负责人: Richard W. CARTHEW
• 金额: $ 29.31万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471590
• 关键词: Actins; Adhesions; Adhesives; Adopted; Cancerous; Cell Shape; Cell membrane; Cells; Cellular biology; Characteristics; Chest; Clinic; Computer Simulation; Dimensions; Drosophila eye; E-Cadherin; Engineering; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Event; Eye; Genetic; Goals; Grant; Illinois; Interdisciplinary Study; Kinetics; Knowledge; Laboratories; Lead; Link; Liquid substance; Location; Measures; Mechanics; Medical; Membrane; Modeling; Molecular; Molecular Biology; Molecular Machines; Morphogenesis; Morphology; Movement; N-Cadherin; Nature; Organelles; Outcome; Pathway interactions; Physics; Publishing; Regenerative Medicine; Relative (related person); Research; Science; Series; Shapes; Site; System; Testing; Time; Tissue Engineering; Tissue Model; Tissues; Universities; Work; in vivo; intercalation; mathematical model; millimeter; nanoscale; pressure; public health relevance; research study; response; viscoelasticity

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.

描述（由申请人提供）：这项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节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尺度（mm）上的形态学之间的联系尚未建立。为了建立这样的联系，该拨款利用了跨学科研究团队的能力，将理查德·卡修（西北大学）团队的细胞生物学和遗传专业知识与萨沙·希尔根费尔特团队的软材料物理和理论力学专业知识相结合（伊利诺伊大学）。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形状和相邻关系，实现被动能量最小化。沿着细胞膜平面的力变得平衡，导致机械平衡。重要的贡献力是由细胞间粘附和肌动蛋白皮质收缩引起的力。我们认为，力的不平衡自然会导致组织系统移动，其中细胞接触和形状的变化导致组织达到局部能量最小值的停滞状态。我们的目标是通过设计某些细胞中的力不平衡并描述静态最终结果来检验这一假设。如果正确的话，则 数学模型将准确预测此类实验的力学结果。进一步扩展该假设，人们可能会认为形态发生是响应力变化而达到的一系列渐进的局部能量最小值。我们的目标是用一个数学模型来测试这个假设，该模型描述了眼睛中一个非常明确的机械路径，其中四个细胞改变彼此的接触。该模型能否预测机械特征以及粘合力和收缩力随时间和位置变化的方式？最后，我们知道组织内存在其他力，但不了解它们对组织力学的相对贡献。为了实现这一目标，我们将开发一个数学模型，该模型还考虑细胞粘弹性、流体压力、基质粘附和细胞器位移。该模型将假设这些力在三个维度上保持平衡，从而实现被动能量最小化。了解组织形态的生物物理性质将对再生医学和组织工程有很大好处。