Multiscale modeling of epithelial tissue dynamics and engineering

上皮组织动力学和工程的多尺度建模

• 批准号: RGPIN-2014-05862
• 负责人: Feng, James
• 金额: $ 2.55万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611888
• 关键词: Multiscale; modeling; epithelial; tissue; dynamics

The prospect of growing artificial tissues and organs in the lab is generating much excitement, with the recent reports of human retina and brain tissues grown from embryonic stem cells. However, great scientific and technical barriers remain to be surmounted before widespread clinical use becomes reality. The potential benefits for health care, where artificial tissues can be implanted to restore, repair, and improve the function of failing natural organs, are as enormous as the challenges are daunting. Progress will hinge on new research in two areas: developmental biology and biomaterials engineering. The research proposed here seeks a nonconventional approach that integrates molecular-genetic information from developmental biology with engineering knowledge of the mechanics of epithelial tissues. This integration is motivated by the fact that biological tissues grow not only according to a genetic blueprint, but also subject to the mechanical forces and deformation in their physical environment. Mechanically, soft tissues often behave in ways that resemble complex fluids and soft solids. The central idea of this proposal is to translate computational methods developed for complex fluids and soft matter to a novel class of problems in the dynamics and growth of epithelial issues. Epithelium refers to the skin that encloses organs and embryos. It is also the key structure that folds during early development of embryos to form internal organs. Toward a quantitative understanding of such processes, we develop a mathematical model that bridges the cellular scale and the much larger tissue scale. A crucial feature of the model is to properly capture the information exchange between the two scales. For example, sustained stress on a skin tissue tends to trigger structural changes in polymers that form the skeleton of each cell, and to dissolve the adhesive connection among neighboring cells. Thus the whole tissue can deform or “flow”. In return, small-scale biochemistry inside a cell produces signaling proteins that control cell division and death, and these events ultimately feed back to the overall behavior of the tissue on the large scale. We further carry out computer simulations of various scenarios of tissue growth, adapting an extensive numerical toolkit that we have developed for the dynamics of complex fluids, interfaces and soft membranes. In scientific terms, we expect two major outcomes from this research. The first is to lay the foundation for a quantitative understanding of epithelium dynamics. In particular, we wish to clarify how mechanical forcing and deformation change the properties of a tissue and affect its ability to grow under laboratory conditions. The second is to develop the ability to solve “inverse problems” in tissue engineering. That is the ability to prescribe optimal experimental conditions and protocols that will produce the desired morphology for a tissue or organ. Such outcomes will be major advances toward the goal of custom-designed artificial organs, with far-reaching health-care benefits for Canada and beyond. A less tangible but equally important benefit of the research will be the specialized training of young scientists in this emerging field. They will be exposed to cutting edge, interdisciplinary research that uses physics and engineering tools to study biology and to inform medicine. This will prepare them for the expanding frontiers of Research and Development in the decades to come.

实验室中生长人造组织和器官的前景引起了很多兴奋，最近关于人类视网膜和脑组织从胚胎干细胞生长的报道。然而，在宽度临床使用成为现实之前，伟大的科学和技术障碍仍有待确认。可以植入人造组织以恢复，修复和改善自然器官的功能的潜在益处，就像挑战令人生畏一样巨大。 进步将取决于两个领域的新研究：发展生物学和生物材料工程。这里提出的研究寻求一种非惯性方法，该方法将生物学的分子遗传信息与上皮组织机械的工程知识相结合。这种整合是由于生物组织不仅根据遗传蓝图生长的事实而动机，而且还遵守其物理环境中的机械力和变形。从机械上讲，软组织通常以类似于复杂的液体和软固体的方式行为。该提案的核心思想是将针对复杂流体和软物质开发的计算方法转化为上皮问题动态和生长中的一系列新问题。 上皮是指包围器官和胚胎的皮肤。它也是在胚胎早期开发过程中折叠以形成内部器官的关键结构。为了对此类过程进行定量理解，我们开发了一个数学模型，该模型桥接了细胞尺度和更大的组织量表。该模型的关键特征是正确捕获两个量表之间的信息交换。例如，对皮肤组织的持续应力倾向于触发形成每个细胞骨骼的聚合物的结构变化，并溶解相邻细胞之间的粘合剂连接。整个组织会变形或“流动”。作为回报，细胞内部的小规模生物化学会产生控制细胞分裂和死亡的信号蛋白，这些事件最终会反馈大范围内组织的整体行为。我们进一步对组织生长的各种情况进行了计算机模拟，并适应了我们为复杂流体，界面和软机制的动力学开发的广泛数值工具包。 从科学的角度来看，我们期望这项研究产生两个重大结果。首先是为上皮动力学的定量理解奠定基础。特别是，我们希望阐明机械强迫和变形如何改变组织的特性，并影响其在实验室条件下生长的能力。第二个是发展在组织工程中解决“反问题”的能力。这就是规定最佳实验条件和方案的能力，该条件将产生组织或器官的所需形态。这样的结果将是朝着定制设计的人工器官的目标，对加拿大及其他地区的医疗保健福利。 研究的一个不太明显但同样重要的好处将是对这个新兴领域的年轻科学家的专业培训。他们将接触到尖端，跨学科研究，该研究使用物理和工程工具来研究生物学和为医学提供信息。这将使他们为未来几十年的研发领域的扩大边界做好准备。