Multiphase Viscoelastic Models of Branching Morphogenesis

分支形态发生的多相粘弹性模型

• 批准号: 9805611
• 负责人: Sharon Lubkin
• 金额: $ 4万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9805611&HistoricalAwards=false
• 关键词: Multiphase; Viscoelastic; Models; Branching; Morphogenesis

Branching morphogenesis, the creation of a hollow tree ofbranched ducts from an initially simple structure, is a robust,important, and widely studied model system in developmentalbiology. There is a large body of experimental results on whatis and is not required to generate the glandular structures, butthere is as yet no single theory which ties together all that isknown about branching morphogenesis. The two main existingtheories hypothesize that the origin and direction of branchingactivity rest solely in, respectively, (1) the epithelium, and(2) the mesenchyme. This study proposes a new hypothesis, thatactivity in (3) both tissues is essential. This study willdevelop a mathematical model of the forces and deformationsinvolved in branching morphogenesis, using a multiphase formulation to track changes in the density of cells, extracellularmatrix components, and interstitial fluid. The model will beanalyzed, using asymptotics, perturbations, bifurcation analysis,parameter estimation, and numerical simulation. The first taskwill be to evaluate the agreement of the model with experimentalfacts, and the second will be to help answer some long-standingquestions, specifically the relative mechanical roles of theepithelium and the mesenchyme. Specific predictions will bemade, that others may test them experimentally. The primary goalof this project is to distinguish between the three majortheories of branching morphogenesis mentioned above. It is verylikely that the insights gained from this modeling study ofbranching morphogenesis will lead to a better under standing ingeneral of the physical forces in confluent (epithelial) andsparse (mesenchymal) tissues, both in homeostasis and indevelopment, with applications and insights in other contextssuch as somitogenesis, tooth and hair formation, angiogenesis,healing, and tumor growth. The study will also lead to animproved understanding of the multiphase models of biologicaltissues which have been developed in other contexts, throughextending these passive models to tissues which are activelygrowing and remodeling. The formation of branched tubular structures occursthroughout an organism, in many different tissues, and isessential to the very existence of large organisms which need totransport fluids more than a short distance. Branchingmorphogenesis is a widespread phenomenon in animal development,generating the form of such organs as the lung, mammary gland,salivary gland, and kidney. Although nearly every technique ofcellular and developmental biology has been applied to it, andmuch has been learned from these experiments, there is stilluncertainty as to the mechanism of branching. The overwhelmingmajority of experiments on branching have concentrated onbiochemical aspects, following the dominant paradigm inbiological research of the last few decades. Yet the essence ofmorphogenesis is that tissues grow and move and change shape, andthis requires physical forces to emerge from the molecularbiology. Hence the next logical step in morphogenesis researchis study of the biomechanical aspects, which are what create andmodify form. A mathematical model will be developed of themechanical forces and resulting material deformations of thetissues involved in morphogenesis. Analysis of the model will(1) allow a comparison of the biomechanical aspects of thecurrently competing theories of branching morphogenesis, (2) leadto greater understanding of the relatively new modelingmethodology itself, which is useful in many other biologicalapplications, and (3) suggest new interpretations and experimentstowards the goal of understanding one of the most importantphenomena in developmental biology.

分支形态发生，即从最初简单的结构产生一个中空的分支导管树，是发育生物学中一个强大的、重要的和广泛研究的模型系统。 有大量的实验结果表明，什么是产生腺结构所必需的，什么不是，但是还没有一个单一的理论把所有已知的关于分枝形态发生的理论联系在一起。 现有的两种主要理论分别假设分支活动的起源和方向仅取决于（1）上皮和（2）间充质。 这项研究提出了一个新的假设，即（3）两种组织的活性都是必不可少的。 本研究将建立一个分支形态发生中的力和变形的数学模型，使用多相公式来跟踪细胞、细胞外基质成分和间质液密度的变化。 该模型将被分析，使用渐近，扰动，分岔分析，参数估计，和数值模拟。 第一个任务是评估模型与实验事实的一致性，第二个任务是帮助回答一些长期存在的问题，特别是上皮和间充质的相对机械作用。 具体的预测将被提出，其他人可以通过实验来测试它们。 本项目的主要目标是区分上述三种主要的分枝形态发生理论。 从分支形态发生的建模研究中获得的见解很可能会导致更好地理解融合（上皮）和稀疏（间充质）组织中的一般物理力，无论是在稳态还是在发育中，以及在其他背景下的应用和见解，如体节发生，牙齿和毛发形成，血管生成，愈合和肿瘤生长。 该研究还将导致对在其他背景下开发的生物组织的多相模型的更好理解，通过将这些被动模型扩展到活跃生长和重塑的组织。 分支管状结构的形成发生在整个生物体的许多不同组织中，并且对于需要在短距离内运输流体的大型生物体的存在是必不可少的。 分支形态发生是动物发育中的一种普遍现象，产生肺、乳腺、唾液腺和肾等器官的形态。 尽管几乎每一种细胞和发育生物学的技术都被应用于它，并且从这些实验中也学到了很多东西，但是关于分支的机制仍然存在不确定性。 在过去的几十年里，大多数关于分支的实验都集中在生物化学方面，遵循生物学研究的主导范式。 然而，形态发生的本质是组织生长、运动和改变形状，而这需要分子生物学中的物理力量。 因此，形态发生研究的下一个合乎逻辑的步骤是研究生物力学方面，这是创造和修改形式。 一个数学模型将被开发的机械力和由此产生的材料变形的组织参与形态发生。 对该模型的分析将（1）允许比较目前相互竞争的分支形态发生理论的生物力学方面，（2）导致对相对较新的建模方法本身的更好理解，这在许多其他生物学应用中是有用的，（3）提出新的解释和实验，以实现理解发育生物学中最重要的现象之一的目标。