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: 8736405
• 负责人: David Bilder
• 金额: $ 29.19万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8736405
• 关键词: 4D Imaging; Animal Organ; Animals; Anisotropy; Automobile Driving; Basement membrane; Behavior; Biological Assay; Biomechanics; Cadherins; Cell Communication; Cells; Complex; Computer Analysis; DNA Sequence Rearrangement; Defect; Development; Disease; Drosophila genus; Epithelial; Epithelium; Equilibrium; Event; Extracellular Matrix; Genes; Genetic; Genetic Screening; Genome; Goals; Growing Follicle; Heterogeneity; Human; Hydrostatic Pressure; Image; 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; in vivo; interstitial; mechanical drive; 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一个简单的器官，动物器官的多样化、复杂但高度可复制的形式对于它们的功能至关重要。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，由细胞与细胞和细胞与细胞外基质（ECM）相互作用等主要影响驱动并对其做出响应。目前，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还很原始。特别是，虽然最近的工作揭示了钙粘蛋白介导的皮质张力如何调节极化细胞行为，但活体动物中有组织的 ECM 产生的力如何驱动器官形态发生仍然知之甚少。这项工作的长期目标是了解基因组如何协调整合在组织内的机械力来驱动特定的三维形状。我们将简单地研究这个问题 果蝇卵室经历了从各向同性形状到沿单轴伸长 2.5 倍的基本发育转变。组织伸长是许多发育中的动物器官中广泛保守且关键的事件，重要的是，果蝇卵伸长涉及细胞-细胞和细胞-基质相互作用。它还涉及集体细胞迁移，从而构建独特的极化 ECM。因此，果蝇卵室位于一个“最佳点”，其复杂性足以捕获主要脊椎动物器官形态发生过程，但又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 产生的各向异性力如何塑造生长中的卵室。我们假设组织旋转构建了具有独特机械特性的平面极化 ECM，并通过各向异性改变细胞间相互作用来指导极化细胞重排。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法相结合来测试这一假设，以测量和操纵所涉及的力。 4D 成像结合定量计算分析、激光切割和力传感生物力学探针将测量组织张力和 ECM 刚性。对无法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。所揭示的机制将有助于我们了解人类发育缺陷和因形态发生机制改变而引起的其他疾病。