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

合作研究：早期哺乳动物胚胎发育：随机建模和实验

• 批准号: 1562078
• 负责人: William Holmes
• 金额: $ 41.86万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1562078&HistoricalAwards=false
• 关键词: Collaborative; Research; Early; Mammalian; Embryo

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.

哺乳动物胚胎发育中的一个关键事件是胚胎与胚胎外结构的构建。最初，单个细胞分裂多次，生成 10-20 个相似细胞的集合体。不久之后，这些前体细胞的后代分化并自组织形成其他结构。该过程的显着特点是其高水平的可重复性，尽管存在许多随机变化的来源。近年来，实验审讯提出了多种理论来解释这一过程的原因。然而，目前还不清楚是什么在驱动组织，特别是是什么导致了组织的稳健性。该项目采用联合实验和建模方法来解决这个问题。在建模方面，将开发一个新颖的计算建模平台，该平台结合了已知和假设的物理和遗传过程，以单独和联合测试它们对发育的影响。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。该框架最初将针对小鼠发育进行开发，随后进行扩展，以确定早期小鼠和人类细胞之间的已知差异如何影响组织，证据表明这种差异在发育中的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线索。该研究还将建立新的原理，说明物理和生化调节过程之间的相互作用如何导致组织和极其复杂的生物体的发育。将开发一个用于研究小鼠和人类早期胚胎发育的多尺度和随机计算框架。此外，该项目还将开展新的培训活动，涉及研究生、本科生和高中生，重点是促进定量思维以及培养建模和仿真技能。该培训将为学生提供研究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项目的优势，以及范德比尔特大学强大的跨学科培训项目以及与少数族裔服务机构的联系。这些项目将相互促进，以促进各个教育层次的多样性。