CAREER: Cellular control through the development of engineered gene circuits

0239165仓促许多基本的细胞过程是由遗传电路，采用蛋白质-DNA相互作用的调节功能。与蛋白质-DNA相互作用相关的反馈回路的生物化学导致非线性效应，非线性分析工具变得非常宝贵。在这个项目中，合成基因振荡器正在细菌细胞中建模和构建。PI旨在将振荡器耦合到固有的周期性细胞过程，这可能导致在细胞蛋白质水平中夹带或诱导网络振荡的可能策略，并证明在与需要放大或精确定时的细胞过程相互作用的网络设计中是有用的。 一个多基因的记忆为基础的合成网络，可以作为一个传感器的多个瞬态信号，从而形成的基础上，一般的控制方案需要一个“如果/然后”的结构，也将被设计和建造。拟议的工程基因电路将导致对复杂生物网络的当前理解的可测试的预测。这种设计合成基因网络的能力提供了一个令人兴奋的前景，即从自然生物中提取精心挑选的子系统，并将建模和实验工作集中在确定孤立子系统的行为上。这项工作的长期目标是建立越来越完整的自然系统行为模型，同时在每个阶段保持在易于处理的实验系统中测试模型的能力。这种方法的强大之处在于，它可以用来研究简化的系统，以便深入了解基因调控的一般“模块”。这些模块包括充当开关或振荡器的子网络，以及用于跨细胞群体进行通信的网络。这项建议所产生的工作将通过以下项目对教育产生影响：（一）为生物信息学方案编制系统生物学课程。为此，工程基因电路的研究将用于形成本科生和研究生系统生物学课程的基础。(ii)小学科学课程的发展。 该计划将在圣地亚哥联合学区内一所拥有大量少数民族成分的学校开发。(iii)招收REU学生。PI每年夏天将积极从NSF本科生研究经验（REU）计划中招募两名学生。

0239165HastyMany fundamental cellular processes are governed by a genetic circuitry that employs protein-DNA interactions in regulating function. The biochemistry of the feedback loops associated with protein-DNA interactions leads to nonlinear effects, and the tools of nonlinear analysis become invaluable. In this project synthetic gene oscillator is being modeled and constructed in bacterial cells. The PI intends to couple the oscillator to an intrinsic periodic cellular process, which could lead to possible strategies for entraining or inducing network oscillations in cellular protein levels, and prove useful in the design of networks that interact with cellular processes that require amplification or precise timing. A multi-gene memory-based synthetic network that can function as a sensor of multiple transient signals, and thus form the basis for general control schemes requiring an "if/then" structure, will also be designed and constructed. The proposed engineered gene circuits will lead to testable predictions regarding the current understanding of complex biological networks. This ability to design synthetic gene networks offers the exciting prospect of extracting carefully chosen subsystems from natural organisms, and focusing both modeling and experimental effort on determination of the behavior of the subsystems in isolation. The long-range goal of such work would be to assemble increasingly complete models of the behavior of natural systems, while maintaining at each stage the ability to test models in a tractable experimental system. The power of this approach is that it can be used to study simplified systems in order to gain insight into the general "modules" of gene regulation. These modules include sub-networks that act as switches or oscillators, as well as networks that act to communicate across a population of cells. Work stemming from this proposal will impact education through the following projects: (i) Development of systems biology curricula for the Bioinformatics Program. To this end, research from engineered gene circuits will be used to form the basis for the systems biology curricula for undergraduate and graduate students. (ii) Development of an elementary school science program. This program will be developed in a school with a large minority component within the San Diego Unified School District. (iii) Recruitment of REU students. The PI will actively recruit two students per summer from the NSF Research Experiences for Undergraduates (REU) Program.