Engineering Advanced Logical Operations for Gene Control

生命系统对环境中的刺激做出反应。这一特点使个性化医学和生物工业应用成为可能。开发这些应用程序的一个障碍是缺乏能够促进复杂操作的调节器(即可以打开或关闭基因的开关)。这个项目将尝试创建一类新的基因调节器，可以执行基本的逻辑运算(即，与、或、非)。这些调节器可以在模仿计算机程序的序列中组合。这些生物程序将指导细胞完成特定的功能。一个例子可能如下：如果检测到化合物E(和)F，则打开基因G；如果E(OR)F单独存在，则不存在G。该项目将通过旨在教育来自未被充分代表的群体的学生进行最先进的生物工程的外联活动来补充。这一倡议将有助于发展一支多元化的科学和工程劳动力队伍，为终身为研究、教育和它们的融合做出贡献奠定坚实的基础。该项目的目标是开发细胞内的组合逻辑门(程序)，以实现对基因转录的多输入信号控制。设想的生物编程将需要创造一类新的DNA结合转录因子。该项目的成功完成将导致一类新的正交和模块化的DNA结合转录因子，它们作为逻辑系统发挥作用。由此产生的系统将允许可编程的微生物决策，其中信号输入的不同组合导致基因输出的不同组合。这些转录因子可以在DNA结合蛋白(或转录因子系统)调控转录的任何位置直接引入现有的遗传回路。该项目的成功完成将导致生物计算能力的显著增强，这将使在细菌自然网络规模上构建合成调控网络成为可能。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Living systems respond to stimuli in the environment. Personalized medicine and bio-industrial applications are made possible by this trait. An obstacle to developing these applications is a lack of regulators (i.e., switches that can turn genes on or off) that can facilitate complex operations. This project will attempt to create a new class of gene regulators that can perform fundamental logical operations (i.e., AND, OR, NOT). These regulators can be combined in sequences that mimic a computer program. These biological programs will direct the cell to fulfill specific functions. One example might be the following: if compounds E (AND) F are detected, then turn on gene G; if E (OR) F are present individually, then NOT G. This project will be complemented by outreach activities aimed at educating students from underrepresented groups in state-of-the-art biological engineering. This initiative will contribute to the development of a diverse engaged science and engineering workforce, building a firm foundation for a lifetime of contributions to research, education and their integration. The goal of this project is to develop combinational logic gates (programs) in cells to implement multiple input signal control over gene transcription. The biological programming envisioned will require the creation of a new class of DNA-binding transcription factors. Successful completion of the project will result in a new class of orthogonal and modular DNA-binding transcription factors that work as logical systems. The resulting system will allow programmable microbial decision making, where different combinations of signal inputs result in distinctive combinations of genetic outputs. These transcription factors can be directly introduced into existing genetic circuits at any position where transcription is regulated by a DNA binding protein (or system of transcription factors). Successful completion of this project will result in a significant enhancement in biological computing capacity, which will enable the construction of synthetic regulatory networks at the scale of natural networks in bacteria.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.