Dynamical maintenance of left-right symmetry during vertebrate development

脊椎动物发育过程中左右对称的动态维持

• 批准号: 10797382
• 负责人: Jonathan David Touboul
• 金额: $ 42.44万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797382
• 关键词: Affect; Anatomy; Animals; Biological; Birth; Breathing; Buffers; Cilia; Congenital Abnormality; Coupled; Data; Data Analyses; Development; Diffusion; Embryo; Embryonic Development; Embryonic Structures; Exhibits; Failure; Gene Expression; Genetic study; Image; Imaging Techniques; Impairment; Lead; Left; Liquid substance; Maintenance; Mediating; Medical; Modeling; Molecular; Movement; Mus; Paraxial Mesoderm; Phase; Physiological; Positioning Attribute; Posture; Preventive measure; Reaction; Research Design; Segmentation Clock Pathway; Side; Signal Transduction; Signaling Molecule; Somites; Specific qualifier value; Spinal; System; Theoretical model; Tretinoin; Vertebral column; Vertebrates; Wild Type Mouse; experimental study; fetal; improved; insight; mathematical model; rib bone structure; scoliosis; simulation; somitogenesis; spatiotemporal; spine bone structure

Broad Objective: Maintaining anatomical symmetry in vertebrates is essential for proper physiological function, and loss of symmetry in ribs and vertebrae can lead to serious conditions such as scoliosis and impairments of appropriate breathing and posture. This project will explore the developmental emergence of left-right symmetry, combining biological experiments on wild-type mice and a model of early loss of symmetry with mathematical models of gene expression and molecule distributions. Through these studies, the project will provide new important insight into the determinants of body (a)symmetry. Specific Aims and Research Design: The somites are the embryonic structures giving rise to the vertebrae and rib cage. They are formed at early phases of embryonic development and emerge progressively in pairs of paraxial mesoderm blocks on both sides of the midline in a highly symmetric manner. The symmetry of the somites is actively maintained through mechanisms controlled by retinoic acid (RA) signaling. Indeed, animals deficient in RA exhibit an asymmetric somite formation. This proposal will investigate this RA-mediated symmetry maintenance mechanisms by combining experiments on RA-deficient mice with mathematical models of somitogenesis. In Aim 1, to investigate the dynamical mechanism of somite formation in wild-type and RA-deficient embryos, we will characterize finely the somite formation timing, period, and positions in mouse embryos through live imaging techniques coupled with and topological data analysis. In Aim 2, to study the genetic mechanism involved in the segmentation clock, which controls the spatio-temporal formation of somites, the same live-imaging setup will be leveraged to extract the dynamics of the segmentation clock in mouse embryos. This data will be used to develop and specify a theoretical model of somitogenesis which will in turn allow exploring the determinants of symmetry maintenance and its breakdown. To explore how asymmetry may arise and be buffered by RA, Aim 3 proposes to study the origin of asymmetry in RA-deficient mouse. It will rely on the development of computational fluid dynamics simulations to analyze the global distribution of key signaling molecules as they are transported in fluids driven by cilia movements. This will be coupled to reaction-diffusion systems and their dynamics will be explored to investigate how RA-mediated mechanism can buffer any initial asymmetry in molecular concentrations.

广泛的目标：在脊椎动物中保持解剖对称性对于适当的生理至关重要 肋骨和椎骨中对称性的功能以及对称性的丧失会导致严重的条件，例如脊柱侧弯和 适当呼吸和姿势的损害。该项目将探索发展的出现 左右对称性，结合了野生型小鼠的生物学实验和早期丧失的模型 与基因表达和分子分布的数学模型的对称性。通过这些研究， 该项目将为身体决定因素（a）对称性提供新的重要见解。 具体目的和研究设计：体积是胚胎结构引起的胚胎结构 椎骨和肋骨笼。它们是在胚胎发育的早期阶段形成的 在中线两侧的一对副介胚层块中逐渐形成高度对称性 方式。通过视网膜控制的机制积极维持体系的对称性 酸（RA）信号传导。实际上，缺乏RA的动物表现出不对称的体积形成。这个建议 将通过将RA缺陷小鼠的实验与体型发生模型相结合，研究这种RA介导的对称性维持机制。 在AIM 1中，研究野生型和RA缺陷中体形成的动力学机制 胚胎，我们将在小鼠胚胎中表征细节的形成时间，周期和位置 通过实时成像技术，结合和拓扑数据分析。在AIM 2中，研究遗传 分割时钟涉及的机制，该机制控制了各个节点的时空形成， 将利用相同的实时成像设置来提取鼠标分割时钟的动力学 胚胎。这些数据将用于开发和指定一个理论模型，该模型将在 转弯允许探索对称维护的决定因素及其故障。探索如何 可能会出现不对称性并被RA缓冲，AIM 3提议研究RA缺陷小鼠中不对称的起源。它将依靠计算流体动力学模拟的开发来分析 关键信号分子在纤毛运动驱动的流体中的全球分布。 这将与反应扩散系统耦合，并将探索它们的动态，以调查如何 RA介导的机制可以缓冲分子浓度中的任何初始不对称。