Shaping of simple organ by anisotropic biomechanical forces

通过各向异性生物力学力塑造简单器官

基本信息

批准号：
9125853
负责人：
David Bilder
金额：
$ 29.18万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9125853
关键词：
4D Imaging Animal Organ Animals Anisotropy Automobile Driving Basement membrane Behavior Biological Assay Biomechanics Cadherins Cell Communication Cells Complex Computer Analysis Defect Development Disease Drosophila genus Epithelial Epithelium Equilibrium Event Extracellular Matrix Genes Genetic Genetic Screening Genome Goals Growing Follicle Health Heterogeneity Human Hydrostatic Pressure Imaging Techniques Individual Investigation Lasers Life Maps Measures Mechanics Mediating Microscopy Morphogenesis Movement Organ Outcome Process Property Proteins Research Rheology Role Rotation Shapes Site Spottings Stereotyping System Testing Tissues Translating Work analog cell behavior cell motility driving behavior driving force egg fly imaging genetics in vivo interstitial mechanical drive mutant nanoindentation polarized cell pressure receptor regional difference sensor tool

项目摘要

DESCRIPTION (provided by applicant): Shaping of a simple organ by anisotropic biomechanical forces the diverse, elaborate but highly replicable forms of animal organs are critical for their functions. Organ forms are generated by a limited set of morphogenetic movements that ultimately involve mechanical forces, driven by and responsive to major influences such as cell-cell and cell-extracellular matrix (ECM) interactions. Our understanding of how these coordinately translate into a force balance that shapes a tissue in vivo is currently primitive. In particular, while recent work has revealed much about how cadherin-mediated cortical tension can regulate polarized cell behaviors, how forces created by organized ECMs in living animals drive organ morphogenesis remains poorly understood. The long-term goal of this work is to understand how the genome orchestrates mechanical forces that are integrated within a tissue to drive a specific three-dimensional shape. We will investigate this question in a simple organ, the Drosophila egg chamber, which undergoes an elemental developmental transition from an isotropic shape to elongate 2.5-fold along a single axis. Tissue elongation is a broadly conserved and critical event in many developing animal organs, and importantly, Drosophila egg elongation involves cell-cell and cell- matrix interactions. It also involves a collective cell migration that builds a distinctive polarized ECM. The Drosophila egg chamber thus lies at a 'sweet spot' with sufficient complexity to capture major vertebrate organ morphogenetic processes but sufficient simplicity and manipulability to elucidate general paradigms. The specific objective of this proposal is to determine how anisotropic forces generated by the ECM sculpt the growing egg chamber. We hypothesize that tissue rotation builds a planar-polarized ECM with distinct mechanical properties, and directs polarized cell rearrangements by anisotropically altering cell-cell interactions. We will test this hypothesis by combining the genetic manipulability of Drosophila with advanced imaging techniques and recently established biomechanical assays to measure and manipulate the forces involved. 4D imaging accompanied by quantitative computational analysis, laser severing and force-sensing biomechanical probes will measure tissue tension and ECM rigidity. Analysis of mutant and manipulated tissues that fail to elongate will reveal causal mechanisms generating protein and mechanical anisotropy, including the role of cell migration. The mechanisms uncovered will inform our understanding of human developmental defects and other diseases arising from altered mechanics of morphogenesis.

描述（由申请人提供）：各向异性生物力学对简单器官的塑造，动物器官的多样化，精致但高度可复制的形式对于它们的功能至关重要。器官形式是由有限的形态发生运动产生的，该运动最终涉及机械力，这些力是由细胞细胞和细胞 - 细胞细胞基质（ECM）相互作用等重大影响驱动和反应的。我们对这些协调如何转化为在体内塑造组织的力平衡的理解是原始的。特别是，尽管最近的工作已经揭示了钙粘蛋白介导的皮质张力如何调节极化细胞行为，但有组织的ECM在活动物中创造的力如何驱动器官形态发生仍知之甚少。这项工作的长期目标是了解基因组如何策划在组织内整合的机械力以推动特定的三维形状。我们将简单地调查这个问题器官，果蝇卵室，从各向同性形状到沿单个轴的延长2.5倍进行元素发育过渡。组织伸长是许多发展中的动物器官中的广泛保守和关键事件，重要的是，果蝇卵的伸长涉及细胞细胞和细胞基质相互作用。它还涉及一个集体细胞迁移，该迁移构建了独特的极化ECM。因此，果蝇卵室位于具有足够复杂性的“最佳点”，可以捕获主要的脊椎动物器官形态发生过程，但具有足够的简单性和可操作性来阐明一般范式。该提案的具体目标是确定ECM生成的卵室产生的各向异性如何产生。我们假设组织旋转构建具有不同机械性能的平面偏振ECM，并通过各向异性改变细胞细胞相互作用来指导极化的细胞重排。我们将通过将果蝇的遗传操作性与先进的成像技术结合在一起，并最近建立的生物力学测定法来测量和操纵所涉及的力来检验这一假设。 4D成像伴随定量计算分析，激光切断和力传感生物力学探针将测量组织张力和ECM刚度。分析突变和操纵的组织无法伸长的组织将揭示产生蛋白质和机械各向异性的因果机制，包括细胞迁移的作用。所发现的机制将为我们对形态发生力学改变的人类发育缺陷和其他疾病的理解提供信息。