Deciphering Principles of Human Embryonic Patterning in Development and Disease

破译人类胚胎发育和疾病模式的原理

• 批准号: 10471048
• 负责人: Berna Sozen
• 金额: $ 150.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471048
• 关键词: 3-Dimensional; Biomedical Engineering; Cell Therapy; Cells; Computer Analysis; Development; Developmental Biology; Disease; Disease model; Embryo; Embryonic Development; Engineering; Environment; Epiblast; Ethics; Event; Genetic; Germ Layers; Human; Human body; Image; In Vitro; Knowledge; Metabolism; Modeling; Molecular; Molecular Conformation; Nutrient; Pathology; Pattern; Prevention; Specific qualifier value; System; Technology; Tissues; adverse pregnancy outcome; base; cell type; design; developmental disease; developmental genetics; early embryonic stage; gastrulation; human disease; human model; human pluripotent stem cell; in utero; innovation; multiple omics; new technology; stem cells; tool

Project Summary/Abstract Fundamental questions in developmental biology revolve around understanding the sequence of molecular and cellular events that regulates lineage specification and differentiation. Nowhere is this more poorly understood than in the early human embryo, which remains experimentally intractable for technical and ethical reasons past the onset of gastrulation - the point when the three major germ layers of the human body are specified within the embryonic epiblast tissue. Myself and others have previously developed stem cell-based systems that recapitulate key aspects of 3-dimensional (3D) mammalian development in vitro, paving the way to a more complete understanding of the specific steps that govern embryonic development. Here, I propose an innovative new experimental approach, using human pluripotent stem cells (hPSCs), combined with cutting-edge bioengineering technologies for a controllable, efficient and scalable modeling of human epiblast development in vitro. This model will permit studying the human germ layer differentiation trajectory and temporal dynamics in the correct 3D-conformation. I will combine state-of-the-art tools in genetics, imaging, and single-cell multi- omics in tandem with high-throughput computational analyses to define the key molecular and cellular events that regulate developmental patterning under different conditions. I will further investigate how these events are controlled by cellular metabolism and nutrient availability, which has important implications for understanding the early embryonic origin of numerous human diseases. My proposal will open up a completely new and powerful experimental paradigm to dissect the fundamental, inter-connected, principles of human developmental genetics at early embryonic stages that are otherwise inaccessible. This new knowledge will also directly inform efforts to efficiently generate mature tissues and cell types from stem cells for disease modeling and cell therapies. Ultimately, these findings will be critical for possible prevention of adverse pregnancy outcomes, offering a unique opportunity to understand the cellular and molecular mechanisms behind developmental disorders and congenital pathologies.

项目总结/摘要 发育生物学中的基本问题围绕着理解分子和 调节谱系特化和分化的细胞事件。没有什么地方比这更不清楚了 由于过去的技术和伦理原因， 原肠胚形成的开始-当人体的三个主要胚层被指定在 胚外胚层组织我和其他人以前已经开发了基于干细胞的系统， 概括了三维（3D）哺乳动物体外发育的关键方面，为更深入地研究哺乳动物的发育铺平了道路。 完全了解控制胚胎发育的具体步骤。在这里，我提出一个创新的 新的实验方法，使用人类多能干细胞（hPSC），结合尖端的 生物工程技术用于人类外胚层发育的可控、有效和可扩展的建模 体外该模型将允许研究人类生殖层分化轨迹和时间动态 在正确的3D构象中。我将联合收割机结合最先进的遗传学成像和单细胞多细胞技术 组学与高通量计算分析相结合，以确定关键的分子和细胞事件 在不同的条件下调节发育模式。我将进一步调查这些事件是如何 由细胞代谢和营养物质的可用性控制，这对理解 许多人类疾病的早期胚胎起源。我的提议将开启一个全新的强大的 实验范式，剖析人类发育遗传学的基本，相互关联的原则， 在早期胚胎阶段，否则无法获得。这些新知识也将直接为以下努力提供信息， 从干细胞中有效地产生成熟组织和细胞类型，用于疾病建模和细胞治疗。 最终，这些发现对于可能预防不良妊娠结局至关重要， 了解发育障碍背后的细胞和分子机制的独特机会， 先天性疾病