Competetive Renewal of MSM: Multiscale Studies of Segmentation in Vertebrates

描述（由申请人提供）：脊柱和骨骼肌来源于被称为体体的胚胎结构，它们从头到尾依次形成。正常的肌肉骨骼发育需要每个体块中正确数量的细胞，并且每个体块获得正确的轴向地址。扰动可导致脊柱畸形，范围从椎体元件的完全紊乱（如脊柱侧凸和脊柱侧凸和发育不良）到脊柱的偏差（前凸、后凸和脊柱侧凸）和骨骼元件区域特征的错误描述（如klipppel - feil综合征）。过去二十年的研究已经发现了分子振荡器和生长因子的梯度，它们被假设控制着某些细胞的大小和特性。然而，对于这些分子参与者如何（或是否）与细胞粘附、增殖和迁移等导致某些细胞模式的细胞行为相关，我们知之甚少。在某种程度上，这种不确定性是由于体细胞发生的时空复杂性、涉及的机制数量以及过去模型和实验之间相对缺乏相互影响。该项目采用多尺度方法来解决这三个问题。美国国立卫生研究院领导的跨机构建模和分析小组（IMAG）已经确定了开发开源、多尺度生物模拟环境和部署集成不同尺度模型的示范项目作为关键目标。该项目将建立脊椎动物体细胞发生的综合三维多尺度预测模型，能够产生和测试关于种间差异机制的特定假设（作为个体间可变性和稳健性的模型）和扰动。它将完善组织模拟环境（CC3D）以提高其对社区的可用性，执行新的生物实验以收集数据作为3D躯体发生模型的输入，并测试模型预测，并使用新兴的多细胞信息共享标准部署模型和实验数据（CBO， CBMSL）。具体而言，它将：1)开发新的3D模型，以整合分子，细胞和组织尺度上的行为，以重现正常的分割动态，并通过使用先进的延时荧光显微镜和基于微流体的梯度细胞技术进行定量测量来测试它们；2)使用一种新的实验范式，允许分割独立于分子“分割时钟”进行研究，以挑战和验证分割模型；3)扩展模型和实验，以了解某些人如何获得位置身份；4)开源以共享格式发布数据和模型。除了生成脊柱发育及其异常的预测模型外，该项目还可以为未来其他器官发育的研究提供支持，并确立多尺度建模在生物医学科学中的作用。它强调模型和数据共享能力，将促进生物建模师和实验人员之间有效地共享资源、工具和模型，大大减少重复工作。

DESCRIPTION (provided by applicant): The vertebral column and skeletal musculature derive from embryonic structures called somites, which form sequentially from head to tail. Normal musculoskeletal development requires the correct number of cells in each somite and that each somite acquires its correct axial address. Perturbations can lead to malformations of the spine ranging from complete disarray of the vertebral elements (e.g. spondylocostal and spondylothoracic dysostoses and dysplasias) to deviations of the spine (lordosis, kyphosis, and scoliosis) and misspecification of the regional identity of skeletal elements (e.g. Klippel-Feil syndrome). Research in the last two decades has uncovered molecular oscillators and gradients of growth factors hypothesized to control somite size and identity. However, little is known about how (or if) these molecular players relate to cell behaviors like cell adhesion, proliferation and migration that result in somite patterning. In part this uncertainty is due to the spatiotemporal complexity of somitogenesis, the number of mechanisms involved and the relative lack of cross-talk between model and experiment in the past. This project undertakes a multiscale approach to address all three issues. The NIH-led Interagency Modeling and Analysis Group (IMAG) has identified as key goals the development of open-source, multi-scale biological simulation environments and the deployment of demonstration projects that integrate models operating at different scales. This project will build comprehensive 3D multiscale predictive models of vertebrate somitogenesis able to generate and test specific hypotheses concerning the mechanisms of interspecies differences (as a model of individual to individual variability and robustness) and perturbations. It will refine a tissue simulation environment (CC3D) to improve its usability to the community, perform new biological experiments to collect data as inputs for 3D somitogenesis models and to test model predictions, and deploy models and experimental data using emerging standards for sharing of multicellular information (CBO, CBMSL). Specifically, it will: 1) develop new 3D models to integrate behaviors at molecular, cellular and tissue scales to reproduce the normal dynamics of segmentation and test them by quantitative measurements using advanced time-lapse fluorescence microscopy and microfluidics-based gradient-cell technology; 2) use a novel experimental paradigm that allows segmentation to be studied independently of the molecular "segmentation clock", for challenging and validating the segmentation models; 3) extend the models and experiments to understand how somites acquire positional identities and 4) open-source release data and models in sharable formats. In addition to generating a predictive model for vertebral column development and its anomalies, this project should enable future studies of the development of other organs and establish the role of multi-scale modeling in biomedical science. Its emphasis on model and data share ability will promote efficient sharing of resources, tools and models among biomodelers and experimentalists, significantly reducing duplication of effort. PUBLIC HEALTH RELEVANCE: Errors in somite segmentation during embryogenesis can lead to malformations and deviations of the spine (e.g., scoliosis, lordosis, kyphosis, spondylocostal and spondylothoracic dysostoses and dysplasias and Klippel-Feil syndrome). Surprisingly little is known about the mechanisms that control somite size, shape, axial identity and pattern in normal development, and consequently about the etiology of congenital disorders of the spine. This project closely couples modeling at multiple scales (molecules, cells, and tissue and body pattern) with novel experimental approaches to validation to produce models that will elucidate disease etiology and identify candidates for genetic screening and diagnostic methods.