Establishing a Rational Design Algorithm for Higher-order Biosensors

智力优势：基因表达的控制是代谢工程、合成基因网络设计、基因功能分析和蛋白质制造的重要工具。迄今为止最成功的方法是基于通过与已知转录效应子的诱导型偶联来调节基因产生。然而，目前一套有用的调控元件缺乏足够的多样性，以推进上述生物技术。因此，新的高阶生物传感蛋白的发明，调节基因表达将催化我们如何进行基础和应用研究在未来十年的革命。现在的挑战是如何翻译有关变构通讯的知识？生物传感的标志转化为合作功能的合理设计协议。 因此，本研究的目的是建立一个创新的合理设计算法，用于创建高阶生物传感元件，是高度敏感和正交的天然功能。研究中产生的新型分子开关将成为天然和非天然系统中令人兴奋的技术的基础。为了实现这一目标，将采用生物启发的工程原理，涉及实验和计算策略以及两者之间的反馈。 该提案中开发的技术将存在于工程，生命科学和信息技术的交叉点。因此，这项研究将通过创造不仅新颖而且有用的生物传感元件来推进工程和生命科学，同时解决互补的科学问题。更广泛的影响：建立一个综合的多学科计划，作为对上述研究计划的补充，同时促进多样性和增加生物工程和科学中代表性不足的群体的参与，将需要制定三个基础和互惠标准，即：i）阐明这项研究计划的总体目标，并表示有兴趣在这些努力中包括代表性不足的群体，以更广泛的社区; ii）在本科生和研究生水平建立严格的培训计划; iii）发展必要的基础设施，以支持这些努力。同样，该计划将存在于大学的使命目标和资源的背景下。反过来，这一努力将为催化本科和研究生教育的文化变革铺平道路，为学生，教师和大学，通过建立一个创新的模式，在超越传统学科界限的研究背景下，在肥沃的环境中促进多样性和培训。这一举措将有助于发展一支多元化的科学和工程队伍，为终身为研究、教育及其整合做出贡献奠定坚实的基础。

Intellectual Merit:The control of gene expression is an important tool for metabolic engineering, the design of synthetic gene networks, gene-function analysis, and protein manufacturing. The most successful approaches to date are based on modulating gene production via an inducible coupling to known transcriptional effectors. However, the current set of useful regulatory elements lacks sufficient diversity to advance the abovementioned biotechnologies. Accordingly, the invention of novel higher-order biosensing proteins that modulate gene expression will catalyze a revolution in how we conduct basic and applied research over the next decade. The challenge now is how to translate knowledge regarding allosteric communication?a hallmark of biosensing?into a rational design protocol for cooperative function. Accordingly, the objective of this study is to establish an innovative rational design algorithm for creating higher-order biosensing elements that are highly sensitive and orthogonal to native functions. The novel molecular switches generated in the study will become the foundation of exciting technologies in natural and non-natural systems alike. To accomplish this objective, bio-inspired engineering principles that involve both experimental and computational strategies with feedback between the two will be employed. The technology developed in this proposal will exist at the intersection of engineering, life science and information technology. Thus, this research will advance both engineering and life sciences via the creation of not only novel but useful biosensing elements in addition to addressing complementary scientific questions.Broader Impacts:Establishing an integrated multidisciplinary program that is complementary to the aforesaid research initiative, while promoting diversity and increasing the involvement of underrepresented groups in biological engineering and science, will require the development of three underpinning and reciprocal criteria, namely: i) articulating the overarching goals of this research program and expressed interest in including underrepresented groups in these efforts to the broader community; ii) establishing a rigorous training initiative at both the undergraduate and graduate level; and iii) developing the necessary infrastructure to support these efforts. Likewise, this program will exist within the context of the mission goals and resources of the University. In turn, this effort will pave the way toward catalyzing a cultural change in undergraduate and graduate education, for students, faculty, and the University, by establishing an innovative model for promoting diversity and training in a fertile environment in the context of research that transcends traditional disciplinary boundaries. 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.