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

• 批准号: 9329300
• 负责人: David Bilder
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329300
• 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; Dimensions; Disease; Drosophila genus; Epithelial; Epithelium; Equilibrium; Event; Extracellular Matrix; Genes; Genetic; Genetic Screening; Genome; Goals; Growing Follicle; 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; egg; fly; imaging genetics; in vivo; interstitial; mechanical force; mechanical properties; mutant; nanoindentation; polarized cell; pressure; public health relevance; receptor; regional difference; sensor; tool

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）：通过各向异性生物力学力塑造简单器官动物器官的多样性，复杂但高度可复制的形式对其功能至关重要。器官形态是由一组有限的形态发生运动产生的，这些运动最终涉及机械力，由细胞-细胞和细胞-细胞外基质（ECM）相互作用等主要影响驱动并对其作出反应。我们对这些如何协调地转化为塑造体内组织的力平衡的理解目前还很原始。特别是，虽然最近的工作已经揭示了很多关于钙粘蛋白介导的皮质张力如何调节极化细胞行为，如何在活体动物中有组织的ECM驱动器官形态发生的力量仍然知之甚少。这项工作的长期目标是了解基因组如何协调整合在组织中的机械力，以驱动特定的三维形状。我们将用一个简单的 器官，果蝇卵室，经历了一个基本的发展转变，从各向同性的形状延长2.5倍沿着一个单一的轴。组织伸长是许多发育中的动物器官中广泛保守和关键的事件，并且重要的是，果蝇卵的伸长涉及细胞-细胞和细胞-基质的相互作用。它还涉及建立独特的极化ECM的集体细胞迁移。因此，果蝇卵室位于一个“甜蜜点”，具有足够的复杂性，以捕捉主要的脊椎动物器官形态发生过程，但足够的简单性和可操作性，以阐明一般的范例。本提案的具体目标是确定ECM所产生的各向异性力如何塑造生长中的卵室。我们假设，组织旋转建立了一个平面极化ECM具有不同的机械性能，并通过各向异性改变细胞-细胞相互作用的极化细胞重排。我们将通过将果蝇的遗传可操纵性与先进的成像技术和最近建立的生物力学测定相结合来测试这一假设，以测量和操纵所涉及的力。4D成像伴随着定量计算分析，激光切割和力传感生物力学探针将测量组织张力和ECM刚度。对不能伸长的突变和操纵组织的分析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。揭示的机制将告知我们对人类发育缺陷和其他疾病的理解，这些疾病是由形态发生的机制改变引起的。