Physics of Living Matter: From Molecule to Embryo

生命物质物理学：从分子到胚胎

• 批准号: 10029359
• 负责人: Sebastian J Streichan
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029359
• 关键词: Advocate; Biological Models; Biophysics; Books; Cell Communication; Cell Shape; Cells; Congenital Abnormality; Cytoskeletal Modeling; Cytoskeletal Proteins; Cytoskeleton; DNA; Data; Defect; Deltastab; Development; Developmental Biology; Embryo; Emerging Technologies; Fluorescence Microscopy; Foundations; Gene Expression Regulation; Genetic; Genetic Models; Genotype; Growth; Heart; Human; Image; Investigation; Language; Lead; Life; Light; Mechanical Stress; Mechanics; Microscopic; Microscopy; Modernization; Molecular; Molecular Biology; Morphogenesis; Organ; Organism; Pattern; Physics; Process; Resolution; Rest; Seminal; Shapes; Technology; Time; Tissues; Trees; cell behavior; congenital heart disorder; genetic information; imaging informatics; interdisciplinary approach; morphogens; predictive modeling; tool; transcription factor

ABSTRACT Organ form is vital for organisms to function properly. This is particularly evident for essential organs such as the human heart where shape defects result in congenital heart disease, a common birth defect. Despite major efforts, we still lack answers to this simple question: how does DNA encode shape? Developmental and molecular biology uncovered the principles of how maternal morphogens setup axes and trigger cascades of gene regulation to precisely determine cell fate patterns. Yet how the interplay of genetic information and mechanical activity orchestrates interaction of cells that shape organs remains elusive. In his seminal book “On growth and form” the polymath D'Arcy Thompson advocated for quantitative analysis of morphogenesis. His ideas where ahead of their time: they predate the genetic revolution, and many tools for quantitative analysis where missing. This proposal seeks to lay the foundations for quantitative morphogenesis, revisiting Thompson's agenda armed with the toolkit of the modern era. For a predictive understanding of morphogenesis, molecular investigation must be extended by quantitative analysis of tissue dynamics at the organ scale. At the organ scale concepts from physics of collective phenomena become relevant to study how thousands of cells streamline their `activity' to generate shape. Connecting developmental biology with physics harbors the promise to uncover new mechanisms at the organ scale. We know the transcription factors that determine fate, and cytoskeletal proteins that execute cell behaviors. Many of these players are conserved across a large portion of the tree of life. On the other hand, we learned shape of materials is determined by physical quantities such as force and mechanical stress. To unfold the full potential of an interdisciplinary approach, we need new tools bridging the gap between genetic players and physical quantitates. This approach will lead the way to the principles of morphogenesis. My team develops break through technology overcoming hurdles of whole organ quantitative analysis. Multi- view light sheet microscopy enables rapid in toto live imaging at subcellular resolution. Tissue cartography dives into the rest-frame of curved tissues and generates a panoramic overview, simplifying data handling and quantitative analysis. We pioneer biophysics-image-informatics to extract quantitative observables from fluorescence microscopy in the language of physics. Leveraging advanced understanding of the early embryo in the advanced genetic model system D. melanogaster, we aim for a comprehensive framework predicting how genotype determines tissue flows during axis elongation. Our approach will have a broad impact: by connecting development with physics we form the foundation of quantitative morphogenesis.

抽象的 器官形态对于生物体的正常运作至关重要。这对于重要器官尤其明显，例如 人类心脏的形状缺陷会导致先天性心脏病，这是一种常见的出生缺陷。尽管主要 经过努力，我们仍然缺乏这个简单问题的答案：DNA 是如何编码形状的？发育和 分子生物学揭示了母体形态发生素如何设置轴并触发级联的原理 基因调控精确决定细胞命运模式。然而遗传信息如何相互作用 机械活动协调塑造器官的细胞相互作用仍然难以捉摸。 博学家达西·汤普森（D'Arcy Thompson）在他的开创性著作《论成长与形态》中提倡定量分析 的形态发生。他的想法超前于时代：它们早于基因革命，并且有许多工具 缺少定量分析。该提案旨在为定量分析奠定基础 形态发生，用现代工具包重新审视汤普森的议程。对于预测 对形态发生的理解，分子研究必须通过定量分析来扩展 器官尺度的组织动力学。来自集体现象物理学的器官尺度概念 与研究数千个细胞如何简化其“活动”以形成形状相关。正在连接 发育生物学与物理学有望在器官尺度上揭示新机制。我们 了解决定命运的转录因子和执行细胞行为的细胞骨架蛋白。许多 这些玩家的大部分都保存在生命树的很大一部分中。另一方面，我们学习了形状 材料的性能由力和机械应力等物理量决定。来完整展开 跨学科方法的潜力，我们需要新的工具来弥合遗传参与者和 物理定量。这种方法将引导我们了解形态发生的原理。 我的团队开发了突破性技术，克服了整个器官定量分析的障碍。多- 查看光片显微镜能够以亚细胞分辨率快速进行整体实时成像。组织制图 深入研究弯曲组织的静止框架并生成全景概览，简化数据处理和 定量分析。我们开创了生物物理学-图像-信息学领域，从其中提取定量可观测值 物理学语言中的荧光显微镜。利用对早期胚胎的先进理解 在先进的遗传模型系统D. melanogaster中，我们的目标是建立一个全面的框架来预测 基因型如何决定轴伸长过程中的组织流动。我们的方法将产生广泛的影响： 将发展与物理学联系起来，我们形成了定量形态发生的基础。