Physics of Living Matter: From Molecule to Embryo.

生命物质物理学：从分子到胚胎。

• 批准号: 10582455
• 负责人: Sebastian J Streichan
• 金额: $ 8.03万
• 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/10582455
• 关键词: Animal Model; Animals; Biological Models; Brain; Cells; Complement; Complex; Cytoskeleton; Defect; Development; Disease; Embryo; Embryonic Development; Ensure; Environment; Exhibits; Failure; Folic Acid; Foundations; Genes; Genetic; Genetic Models; Health; Human; Human Genetics; In Vitro; Investigation; Link; Live Birth; Measurement; Measures; Mechanical Stress; Mechanics; Molecular Analysis; Monitor; Morphogenesis; Neural Tube Closure; Neural Tube Defects; Neural tube; New Territories; Organ; Organism; Pattern; Physics; Positioning Attribute; Process; Reproducibility; Severities; Shapes; Structure; Tissues; Tube; Vertebral column; Work; analog; cell behavior; effective therapy; human model; human stem cells; human tissue; in vivo; morphogens; neurodevelopment; progenitor; programs; stem cell based approach; stem cell model; stem cells; stillbirth; success; treatment strategy

ABSTRACT Shape is critical for proper organ function. For example, neural tube morphogenesis lays the foundations of brain and spine. Neural tube defects that fail to close the tube have devastating consequences for the body. Despite success with folic acid treatment, we are still missing effective treatment strategies. From genetic model systems, we have learned much about the principles of how morphogens setup body axes, and trigger a cascade of regulatory factors that precisely pattern the organism, endowing each cell with a unique fate. However, morphogenesis, the question of how genes instruct form, also involves aspects of mechanics. Tissue folding requires the coordinated action of forces that dramatically change the form of the organ. From single cell studies in vitro, we have learned how cells utilize fundamentally dynamic processes that involve their cytoskeleton to generate forces. However, how forces are coordinated across tissues to reliably generate form remains elusive. Progress requires extending molecular analysis to investigation of cellular dynamics at the organ level, to study the interplay of forces and cell behaviors. Organ shape is instructed by patterns of forces generated from dynamic processes observed in cell behaviors. While we are beginning to monitor the dynamics of cell behaviors, measuring these force patterns in animal model systems remains very challenging. Moreover, animal development differs in key aspects from humans. This is particularly true for neural development, and its derived structure the brain. To overcome these hurdles, we have developed a new stem cell model for neural tube closure in a human genetic context. Our approach is inspired by embryogenesis, and first organizes cells into a closed sheet surrounding a lumen. In this way we guide stem cells in terms of fate and form, but leave enough room for a dynamic, and self-organized morphogenetic program. The results are multiple complex and interacting human tissues, which exhibit striking similarity to the in vivo analogue in terms of genetic pattern, shape, and reproducibility. This proposal seeks to enter new territory in the study of mechanical aspects of neural tube closure in a human genetic context. To this end, we exploit the unique capabilities of our stem cell model system to undergo complex morphogenetic processes in the precisely controlled and for quantitative measurements highly suitable environment of a petri dish. Specifically, this environment allows us to directly measure absolute levels of forces in a faithful stem cell model of human neural tube closure. In addition, this setup allows us to investigate how cells handle geometric constraints at the tissue level – a process that has been linked with one of the most devastating forms of neural tube closure defects. Our stem cell-based approach will open up new paths towards deciphering how human genetics works in health and disease.

摘要 体型对于器官的正常功能至关重要。例如，神经管的形态发生奠定了 大脑和脊椎。神经管缺陷如果不能关闭神经管，会对身体造成毁灭性的后果。 尽管叶酸治疗取得了成功，但我们仍然缺乏有效的治疗策略。来自基因 模型系统，我们已经学习了很多关于形态生成器如何设置体轴和触发 一连串的调控因素精确地塑造了有机体，赋予了每个细胞独特的命运。 然而，形态发生，也就是基因如何指导形成的问题，也涉及到力学的各个方面。组织 折叠需要力量的协调作用，这些力量极大地改变了器官的形状。从单人 在体外的细胞研究中，我们已经了解了细胞是如何利用基本的动态过程的，这涉及到他们的 细胞骨架来产生力量。然而，组织间的力是如何协调以可靠地产生形态 仍然难以捉摸。进展需要将分子分析扩展到细胞动力学的研究 器官水平，研究力和细胞行为的相互作用。 器官的形状是由在细胞行为中观察到的动态过程产生的力的模式来指示的。 当我们开始监测细胞行为的动态时，在动物身上测量这些力模式 模型系统仍然非常具有挑战性。此外，动物的发育在关键方面与人类不同。 对于神经发育及其派生结构大脑来说尤其如此.为了克服这些障碍， 我们已经开发了一种新的干细胞模型，用于在人类遗传背景下关闭神经管。我们的方法是 受胚胎发生的启发，首先将细胞组织成围绕管腔的闭合薄片。通过这种方式，我们 引导干细胞在命运和形式方面，但留出足够的空间，动态的，自组织的 形态发生程序。其结果是产生了多种复杂和相互作用的人体组织，这些组织表现出惊人的 在遗传模式、形状和重复性方面与体内类似物相似。 这项提议寻求进入人类神经管闭合的机械方面的研究的新领域。 遗传背景。为此，我们利用我们干细胞模型系统的独特能力来经历 精确控制和高度定量测量中的复杂形态发生过程 培养皿适宜的环境。具体地说，这种环境允许我们直接测量绝对水平 在人类神经管关闭的忠实干细胞模型中的作用力。此外，此设置允许我们 研究细胞如何在组织水平上处理几何约束--这一过程与 最具破坏性的神经管闭合缺陷。我们基于干细胞的方法将开启新的 破译人类基因如何在健康和疾病中发挥作用的途径。