MSM - Multiscale Studies of Segmentation in Vertebrate *

描述(由申请人提供)： 在脊椎动物中，胚胎发育早期的节段形成体节，即沿前后轴分布的反复出现的组织单元。节段性结构形成肋骨、椎骨、四肢、相关肌肉以及中枢和周围神经系统。分割失败可能是致命的，或导致严重的发育异常。体细胞发生依赖于分子时钟、生长因子梯度以及细胞黏附和细胞外基质(ECM)分子的表达。分割需要细胞和细胞外基质复杂、大规模(毫米)的协调运动。尽管人们对分段背后的分子机制的了解越来越多，但相互作用 在体细胞发生过程中分子、细胞和组织水平的机制仍然不清楚。由于亚细胞和大尺度过程之间的紧密反馈，没有一个单一尺度的模型可以模拟体细胞发生。目前的模型只涉及亚细胞或宏观层面，而且是分开进行的。一个成功的多尺度模型将回答发育生物学的一个重大悬而未决的问题：命运决定的分子机制如何与大规模的组织变形相耦合？这项拟议的工作将检验这一假设，即在分割过程中，物理力和生物材料特性必须与移动的生物振荡器-分割时钟-协调，才能成功地进行体细胞发生。我们将对关键的发育机制进行建模和实验，范围从细胞黏附蛋白的局部调节(微米)到整体组织变形(毫米)。我们将开发新的理论和建模方法来弥合这些规模。我们的方法有四个主要组成部分：1)在每个尺度上识别(发现)机制和相关模型。2)确定各层次模型的参数。3)验证 模型结果。4)测试正常和异常行为的模型预测，例如黏附分子的抑制或过度产生。这项研究将产生的技术和见解将适用于其他发展过程。我们开发的软件将形成一个开源、多尺度和通用的组织模拟工具包的核心，其他研究人员可以将其应用于这个和其他发展问题。这项拟议的研究通过解决发育畸形的一个重要子集的原因，为公共卫生做出了贡献。在美国，每年约有15万名婴儿出生(每28个婴儿中就有一个)发生发育畸形。体节形成障碍导致Klippel-Feil综合征、脊柱肋骨发育不良、Jarcho-Levin综合征、先天性脊柱侧弯和后凸、Goldenhar综合征和脊柱裂等疾病。研究可持续发展 脊椎构型的机制将有助于识别正常体格发生的保护性或潜在的破坏性因素，并可能影响预防脊椎构型障碍的治疗。

DESCRIPTION (provided by applicant): In vertebrates, segmentation during early embryogenesis forms somites, recurring tissue modules, distributed along the anterior-posterior axis. Segmental structures give rise to the ribs, vertebrae, limbs, associated muscles, and central and peripheral nervous system. Failures in segmentation can be lethal or cause serious developmental abnormalities. Somitogenesis relies on a molecular clock, growth factor gradients and the expression of cell-adhesion and extracellular matrix (ECM) molecules. Segmentation requires complex, large-scale (millimeter) coordinated movement of cells and ECM. Despite increasing knowledge of the molecular mechanisms underlying segmentation, the interplay of molecular-, cell- and tissue-level mechanisms during somitogenesis remains obscure. Because of the tight feedback between subcellular and large-scale processes, no single-scale model can simulate somitogenesis. Current models address only the subcellular or macroscopic levels and do so separately. A successful multiscale model will answer one of developmental biology's great open problems: how do the molecular mechanisms of fate determination couple to large-scale tissue deformations? The proposed work will test the hypothesis that during segmentation, physical forces and biomaterial properties must coordinate with a moving biological oscillator, the segmentation clock, for successful somitogenesis. We will both model and conduct experiments on key developmental mechanisms ranging from local regulation of cell adhesion proteins (micrometers) to global tissue deformations (millimeters). We will develop novel theories and modeling approaches to bridge these scales. Our methodology has four major components: 1) Identifying (discovering) mechanisms and relevant models at each scale. 2) Determining the parameters for each level of model. 3) Validating model results. 4) Testing model predictions of normal and abnormal behaviors, e.g. inhibition or overproduction of adhesion molecules. The techniques and insights the research will produce will apply to other developmental processes. The software we develop will form the core of an open-source, multiscale and general purpose Tissue Simulation Toolkit, which other researchers can apply to this and other developmental problems. The proposed research contributes to public health by addressing the causes of a significant subset of the developmental malformations which occur in approximately 150,000 infants born each year in the USA (1 out of 28 births). Disturbing somite formation results in Klippel-Feil syndrome.spondylocostal dysostosis.Jarcho-Levin syndrome, congenital scoliosis and kyphosis, Goldenhar syndrome, and spina bifida, among others disorders. Studying the developmental mechanisms in vertebral patterning will aid in the identification of protective or potentially disruptive factors for normal somitogenesis and could potentially impact treatments for the prevention of vertebral patterning disorders.