Collaborative Research: Early Mammalian Embryo Development: Stochastic Modeling and Experiments

哺乳动物胚胎发育中的一个关键事件是胚胎结构与胚胎外结构的构建。最初，单个细胞分裂多次以产生10-20个类似细胞的聚集体。不久之后，这些前体细胞的后代分化并自我组织形成其他结构。这个过程的显着特点是它的高水平的再现性，尽管有一些来源的随机变化。近年来，实验性审讯提出了多种可能导致这一过程的理论。然而，目前还不清楚是什么驱动着组织，特别是什么对组织的健壮性负责。该项目采取了联合实验和建模的方法来解决这个问题。在建模方面，将开发一个新的计算建模平台，将已知和假设的物理和遗传过程结合起来，以单独和联合测试它们对发展的影响。在实验方面，将对小鼠胚胎进行成像和图像分析，以告知该模型并测试其预测。该框架最初将与小鼠发育相关，随后将扩展到确定早期小鼠和人类细胞之间的已知差异如何影响组织，证据表明这在发育人类胚胎中不太稳健。该项目将为哺乳动物植入前如何从单细胞形成提供新的见解。这项研究还将为物理和生物化学调节过程之间的相互作用如何导致组织的发展建立新的原则。将开发一个多尺度和随机计算框架来研究小鼠和人类早期胚胎发育。此外，本项目将开发新的培训活动，涉及研究生，本科生和高中生，重点是促进定量思维和开发建模和模拟技能。这项培训将使学生掌握调查复杂系统所需的计算和系统级方法。这些活动将利用加州大学欧文分校计算系统生物学本科生和研究生培训计划的优势，以及范德比尔特大学强大的跨学科培训计划和与少数民族服务机构的联系。这些方案将相互影响，以促进各级教育的多样性。

A critical event in mammalian embryo development is construction of embryonic versus extra embryonic structures. Initially, a single cell divides multiple times to generate an aggregate of 10-20 similar cells. Soon after, the progeny of these precursor cells differentiate and self-organize to form other structures. The remarkable feature of this process is its high level of reproducibility despite a number of sources of stochastic variation. In recent years, experimental interrogation has suggested multiple theories for what might be responsible for this process. It is still unclear, however, what drives organization, and in particular, what is responsible for its robustness. This project takes a joint experimental and modeling approach to address this issue. On the modeling side, a novel computational modeling platform will be developed that incorporates known and hypothesized physical and genetic processes to test their influence individually and jointly on development. On the experimental side, imaging and image analysis will be performed on mouse embryos to inform this model and test its predictions. This framework will be initially developed in relation to mouse development and later extended to determine how known differences between early mouse and human cells influence organization, which evidence suggests is less robust in developing human embryos.This project will shed new light into how mammalian pre-implantation forms from a single cell. The research will also establish new principles for how the interplay between physical and biochemical regulatory processes leads to development of tissues an organisms of exquisite complexity. A multi-scale and stochastic computational framework to study both mouse and human early embryo development will be developed. In addition, this project will develop new training activities involving graduate, undergraduate, and high school students with an emphasis on promoting quantitative thinking and developing modeling and simulation skills. This training will equip students with computational and system-level approaches needed to investigate complex systems. The activities will take advantage of the strengths of the undergraduate and graduate training programs in computational systems biology at the University of California, Irvine and the strong interdisciplinary training programs and ties with minority serving institutions at Vanderbilt University. These programs will be cross-pollinated to promote diversity at all educational levels.