Signaling dynamics in the control of ectoderm patterning and morphogenesis

控制外胚层模式和形态发生的信号动力学

• 批准号: 10623412
• 负责人: Aryeh Warmflash
• 金额: $ 38.1万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623412
• 关键词: 3-Dimensional; Anterior; Cells; Congenital Abnormality; Development; Ectoderm; Embryo; Engineering; Ethics; Event; Fibroblast Growth Factor; Human Development; Infertility; Lateral; Medial; Methods; Modeling; Morphogenesis; Movement; Nervous System; Neural Crest; Neural Tube Closure; Neural tube; Organ; Organizational Models; Pathway interactions; Pattern; Recovery; Reporter; Reproducibility; Sensory; Shapes; Signal Transduction; Skin; Spontaneous abortion; System; Tissue Sample; Tissues; experimental study; human model; human pluripotent stem cell; implantation; insight; intercellular communication; morphogens; self organization; two-dimensional

Project Summary Neurulation is a crucial stage in human development when the nervous system is patterned, and the neural tube is shaped. A large fraction of severe birth defects as well as post-implantation spontaneous abortions occur at this stage. Despite its importance, this stage of human development is almost completely inaccessible as IVF embryos cannot be cultured until this point, and recovery of tissue samples from these early stages is rare. Even if such methods were possible, they present ethical dilemmas. A powerful emerging alternative is to create self- organizing models of these events starting from human pluripotent stem cells (hPSCs). We have created a two- dimensional system that mimics the early patterning of the ectodermal medial-lateral axis and is ideal for studying self-organization of ectodermal fates which include the nervous system, skin, neural crest, and sensory organs. We have also built upon this system to create a controlled three-dimensional system that undergoes reproducible morphogenesis reminiscent of neural tube closure. Here we propose to refine these models, as well as to create new models of the anterior-posterior axis, and to use these models together with live cell reporters to probe the interplay between morphogen signaling through the Wnt, BMP, and FGF pathways, patterning along the anterior- posterior (AP) and medial-lateral (ML) axes, and neural tube morphogenesis. We will address key questions about how spatial patterns of morphogen signals are organized and how they are interpreted by cells to give rise to patterns of fates and the physical movements that shape tissues. Taken together, these experiments will provide insight into ectodermal patterning and morphogenesis and establish a system for studying birth defects associated with this stage of development.

项目摘要 神经系统是神经系统的图案和神经管时的人类发育的关键阶段 是形状的。大量严重的出生缺陷以及植入后自发流产发生在 这个阶段。尽管它很重要，但人类发展的这一阶段几乎完全无法接近IVF 在这一点之前，不能培养胚胎，并且很少有从这些早期阶段的组织样品恢复。甚至 如果可以使用这种方法，它们会带来道德困境。一个有力的新兴替代方案是创建自我 这些事件的组织模型从人类多能干细胞（HPSC）开始。我们创建了两个 模仿外皮内侧轴的早期模式的尺寸系统，非常适合研究 外皮命运的自组织，包括神经系统，皮肤，神经rest和感觉器官。 我们还构建了该系统，以创建一个受控的三维系统，该系统经历可再现的。 形态发生让人联想到神经管闭合。在这里，我们建议完善这些模型，并创建 前后轴的新模型，并将这些模型与活细胞记者一起使用以探测 通过Wnt，BMP和FGF途径之间的形态学信号传导之间的相互作用，沿着前 - 后（AP）和内侧（ML）轴以及神经管形态发生。我们将解决关键问题 关于如何组织形态学信号的空间模式以及细胞如何解释它们产生 到命运的模式和塑造组织的身体运动。两者一起，这些实验将 提供对外胚层模式和形态发生的见解，并建立一个研究出生缺陷的系统 与这一发展阶段有关。