Using Simulations to Explore Genetic Networks

该项目继续开发计算机方法，将实验绘制的遗传相互作用图转化为现实的，详细的，正式的数学模型，使生物学家能够探索基因是否以及如何在调控网络中相互作用，奠定了蛋白质的条纹空间模式，这些模式预示了后来发展的分段身体计划。 在世界各地的许多实验室中，大约1200人-年的实验研究最终详细了解了所谓的片段极性基因如何在早期果蝇胚胎中相互交叉调节。该项目将这些数据合成到一个系统级模型中，该模型量化了这些基因之间的相互作用，这些基因主要在果蝇中表现出来，但被认为是所有高等动物所共有的，它们协同作用，使这个网络具有惊人的鲁棒性。也就是说，系统级模型预测网络可以继续正确地执行任务，即使其基因之间的所有相互作用的强度发生了很大变化。该项目需要完善该案例研究，并创建另一个基因网络（神经网络）的新模型。该项目将确定在第一个网络中发现的这种鲁棒性是否也发生在其他实验研究良好的网络中。它将使用计算机建模来确定这种鲁棒性是如何演变的。这项研究将包括对真实的果蝇胚胎的实验，以确定计算机模型预测的基因网络可能具有的鲁棒性是否真的存在于真实的胚胎中。活胚胎中的基因网络是否以及如何与遗传和环境变异相抗衡？ 胚胎真的经历了大量的“发育噪音”吗？如果是的话，发育机制是如何利用或隔离这些变异的？这个跨学科的项目将尝试使用实验发育生物学，激光扫描共聚焦显微图像数据的计算机实现的3-D分析，详细的现实数学模型的实现，用于求解微分方程系统的计算机算法和搜索/可视化其相关的高维参数空间的混合来回答这些问题。

This project continues development of computer methods for translating experimentally charted maps of genetic interactions into realistic, detailed, formal mathematical models that allow biologists to explore whether and how genes, interacting in regulatory networks, lay down stripedspatial patterns of proteins which prefigure the segmented body plan that later develops. Approximately 1200 person-years of experimental research, in many labs worldwide, have culminated in a detailed understanding of how the so-called segment polarity genes cross regulate each other in early fruit fly embryos. This project synthesizes those data into a systems-level model that quantifies how the interactions between these genes, characterized principally in fruit flies, but thought to be shared by all higher animals, act synergistically to endow this network with astonishing robustness. That is, the systems level model predicts that the network can continue toperform its task correctly even when the strengths of all the interactions between its genes change greatly. The project entails refinement of that case study, and creation of a new model of another gene network (the neurogenic network). The project will ascertain whether this robustness,found in the first network so modeled occurs also in other experimentally well studied networks. It will use computer modeling to ascertain how such robustness could have evolved. The research will include experiments on real fruit fly embryos to find out whether the robustness, which the computermodel predicts the gene network could have, actually exists in real embryos. Do, and how do, gene networks in living embryos contend with genetic and environmental variation? Do embryos actually experience significant amounts of "developmental noise", and if so, how do developmental mechanisms either exploit or insulate themselves from such variation? This cross-disciplinaryproject will try to answer such questions using a blend of experimental developmental biology, computer-implemented 3-D analysis of laser scanning confocal micrographic data, implementation of detailed realistic mathematical models, computer algorithms for solving differential equationsystems and searching/visualizing their associated high-dimensional parameter spaces.