Integrating cell identities and morphodynamics through extracellular cues

通过细胞外线索整合细胞身份和形态动力学

基本信息

批准号：
10644461
负责人：
Dong-Yuan Chen
金额：
$ 12.85万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644461
关键词：
3-Dimensional Anterior Applied Skills Architecture Atlases Award Basement membrane Cell Lineage Cells Chromosome Mapping Cues Defect Development Distal Embryo Embryonic Development Endoderm Epiblast Epithelium Event Extracellular Matrix Failure Fertilization Fluorescent in Situ Hybridization Foundations Gene Expression Profile Genes Genomic approach Genomics Germ Layers Heterogeneity Human Image In Situ In Situ Hybridization In Vitro Individual Learning Maps Mechanics Mentors Mesenchymal Modeling Molecular Morphogenesis Mus New Territories Pattern Pattern Formation Phase Play Pregnancy Primitive Streaks Process Reaction Regulation Research Resolution Role Shapes Specific qualifier value System Techniques Technology Testing Time Tissues Training Visceral Work blastocyst cell behavior cell fate specification cell motility early pregnancy early pregnancy loss extracellular gastrulation gene function genetic manipulation genome-wide image processing imaging approach implantation in silico in vivo loss of function mammalian embryology mathematical model migration molecular asymmetry mortality natural Blastocyst Implantation new technology novel therapeutic intervention novel therapeutics preimplantation prevent programs quantitative imaging skills stem cell model stem cells tool transcriptomics

3-Dimensional Anterior Applied Skills Architecture Atlases Award Basement membrane Cell Lineage Cells Chromosome Mapping Cues Defect Development Distal Embryo Embryonic Development Endoderm Epiblast Epithelium Event Extracellular Matrix Failure Fertilization Fluorescent in Situ Hybridization Foundations Gene Expression Profile Genes Genomic approach Genomics Germ Layers Heterogeneity Human Image In Situ In Situ Hybridization In Vitro Individual Learning Maps Mechanics Mentors Mesenchymal Modeling Molecular Morphogenesis Mus New Territories Pattern Pattern Formation Phase Play Pregnancy Primitive Streaks Process Reaction Regulation Research Resolution Role Shapes Specific qualifier value System Techniques Technology Testing Time Tissues Training Visceral Work blastocyst cell behavior cell fate specification cell motility early pregnancy early pregnancy loss extracellular gastrulation gene function genetic manipulation genome-wide image processing imaging approach implantation in silico in vivo loss of function mammalian embryology mathematical model migration molecular asymmetry mortality natural Blastocyst Implantation new technology novel therapeutic intervention novel therapeutics preimplantation prevent programs quantitative imaging skills stem cell model stem cells tool transcriptomics

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项目摘要

PROPOSAL SUMMARY/ABSTRACT Establishing proper cell identities and tissue architecture during early embryogenesis is crucial for a successful pregnancy. Coordination of these processes is integral to patterning the mammalian embryos as they increase complexity from the implantation stages. However, how this tight coordination is regulated remains poorly understood. A high rate of mortality seen in human embryos during the first 2-3 weeks post-fertilization is a major cause of early pregnancy loss, yet the essential cellular, molecular, and mechanical changes remain almost entirely uncharacterized. Rather than merely a structural component that provides physical support, recent studies have shown that the extracellular matrix (ECM) has emerging roles in regulating cell fate specification and morphogenesis. My recent work reveals that the embryonic basement membrane (BM), a specialized ECM, plays an essential role in patterning the early post-implantation mammalian embryo. My preliminary results lay the foundation of my proposal to determine how the BM coordinates the collective cell behaviors and facilitates pattern formation at critical developmental stages of early mammalian embryogenesis. We will apply novel technologies, including 4D quantitative imaging and single-cell spatial genomics, combined with in vivo, in vitro, and in silico approaches to test the hypothesis that the BM facilitates embryo patterning through coordinating cell fate specification and tissue morphodynamics. In my first aim, we will comprehensively map the cell behaviors and the morphodynamics of the developing embryos with 3D quantitative imaging and timelapse imaging approaches. We will define the role of the BM through genetic manipulations in stem cell-derived embryo-like models as well as in the natural embryos. In my second aim, we will map the BM organization and apply single-cell spatial transcriptomics approaches to generate in situ fate maps. We will functionally test how the BM regulates cell identities by quantitatively defining gene expression patterns with BM architecture and validate the findings with loss-of-function analyses. Next, we will build mathematical models that integrate cell identities and cell dynamics with the BM mechanics to uncover mechanisms of pattern formation. In my third aim, we will apply the technologies and tools developed in the previous two aims to explore the roles of the BM in shaping the formation of germ layers during gastrulation. Overall, my proposed work will increase our understanding of how extracellular cues facilitate a successful pregnancy and could inspire novel therapeutic approaches to prevent early pregnancy loss. The training provided by this award will allow me to acquire the necessary skills to develop my independent research program to apply a quantitative systems-level approach to uncover the dynamics, functions, and regulations that shape the embryos at critical stages of early pregnancy.

提案摘要/摘要早期胚胎发生期间建立适当的细胞身份和组织结构对于A至关重要成功怀孕。这些过程的协调是对哺乳动物胚胎的模式不可或缺的一部分增加植入阶段的复杂性。但是，如何调节这种紧密的协调理解不佳。在施肥后的前2-3周内，人类胚胎中的死亡率很高。早期妊娠丧失的主要原因，但是必要的细胞，分子和机械变化仍然存在几乎完全没有特色。最近的研究表明，而不是仅仅提供物理支持的结构成分细胞外基质（ECM）在调节细胞命运规范和形态发生方面具有新兴的作用。我的最近的工作表明，专门的ECM胚胎地下室膜（BM）起着至关重要的作用在植入早期植入哺乳动物胚胎时进行构图。我的初步结果奠定了我的基础建议确定BM如何协调集体细胞行为并促进模式形成早期哺乳动物胚胎发生的关键发育阶段。我们将应用新型技术，包括4D定量成像和单细胞空间基因组学，结合体内，体外和计算机方法，以测试BM促进胚胎的假设通过协调细胞命运规范和组织形态动力学的模式。在我的第一个目标中，我们将全面绘制带有3D发育胚胎的细胞行为和形态动力学定量成像和时间解体成像方法。我们将通过遗传来定义BM的作用干细胞衍生的胚胎样模型以及天然胚胎中的操纵。在我的第二个目标中，我们将绘制BM组织并应用单细胞空间转录组学方法来产生原位命运地图。我们将通过定量定义基因表达来测试BM如何调节细胞身份具有BM体系结构的模式，并通过功能丧失分析来验证发现。接下来，我们将建造将细胞身份和细胞动力学与BM力学相结合以发现的数学模型图案形成的机理。在我的第三个目标中，我们将应用在前两个旨在探索BM在胃胃过程中塑造细菌层的形成中的作用。总体而言，我的拟议工作将增加我们对细胞外提示如何促进成功的理解怀孕，可以激发新的治疗方法，以防止早期怀孕。提供的培训通过这个奖项，我可以掌握必要的技能来制定我的独立研究计划以申请一种定量系统级别的方法，以揭示塑造动力学，功能和法规在怀孕早期关键阶段的胚胎。