CAREER: Evolution and Engineering of Cellular Bet-hedging Devices

职业：蜂窝投注对冲设备的演变和工程

• 批准号: 1350949
• 负责人: Ahmad Khalil
• 金额: $ 76万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1350949&HistoricalAwards=false
• 关键词: CAREER; Evolution; Engineering; Cellular; Bet

The award, funded by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences, addresses a classic problem in evolutionary biology: understanding how organisms adapt in ever-changing environments. Many organisms rely on bet-hedging strategies to deal with unpredictable and fluctuating environments. This widespread biological trait underlies diverse phenomena from antibiotic tolerance in bacteria to immune diversity in mammals. For example, a microbial population can enhance its fitness by allowing individual cells to stochastically transition among multiple phenotypes. The resulting population diversity ensures that some cells are well-adapted for an unforeseen environmental change. Uncovering these adaptive switching mechanisms is key to understanding microbial evolution and life in ever-changing environments. Recently, it was proposed that prions - originally discovered as the cause of neurodegenerative diseases in mammals - are bet-hedging elements in fungi, maintained to promote survival in fluctuating environments. Prion proteins can switch between multiple conformational states. Conversion to a prion state has been shown to generate new, heritable phenotypes, which are beneficial in many conditions. The overarching goal of this project is to test the prion bet-hedging hypothesis. According to theory, phenotypic switching rates of bet-hedging elements evolve to be in tune with the rate of environmental fluctuations. A central focus of the project will be to test these predictions by studying prion switching in prescribed, fluctuating environmental selection. A second focus will be to use synthetic biology approaches to de novo engineer prion bet-hedging devices, thereby exploring how adaptive properties might be encoded in these elements. These studies will require the development of new genetic tools, as well as innovative technologies, such as microfluidic platforms, for simulating complex environments and studying cells in ways that are beyond the capabilities of traditional biological experimentation. This work will have broad implications for our basic understanding of evolution, development, and cellular systems. The project will also shed light on the diverse roles of prions, unique elements that are emerging to be common in the microbial world. Finally, the proposed work will have a transformative impact on synthetic biology, enabling new schemes for rationally engineering a wide array of cellular functions.The focus on multidisciplinary approaches, both experimental and theoretical, will provide exciting opportunities for students of all levels to contribute to this largely unexplored, but significant, area of biology. A broad goal of the project is to inspire and train students from K-12 to graduate school to think conceptually about how quantitative, interdisciplinary, and engineering approaches can help in understanding life. Among the specific activities to be pursued, K-12 education will be impacted by developing a 'systems & synthetic biology bootcamp' for Boston University's Summer Challenge, a residential summer program for high school students. The hands-on activities developed will be translated to a broad high school audience via the Inspiration Ambassadors Program. At the undergraduate level, iGEM activities will be expanded and several undergraduates per year will be mentored via the project. At the graduate level, a new integrated course on quantitative systems biology will be developed. Finally, the project will promote exciting technological developments for miniaturizing and automating biological experimentation within lab-on-a-chip systems. Infrastructure for making device designs and operating software freely-available will be implemented in order to make the technology widely accessible and allow students the opportunity to readily prototype ideas.

该奖项由分子和细胞生物科学部的系统和合成生物学计划资助，解决了进化生物学中的一个经典问题：了解生物体如何适应不断变化的环境。许多有机体依靠更好的对冲策略来应对不可预测和波动的环境。从细菌对抗生素的耐受性到哺乳动物的免疫多样性，这种广泛的生物学特征是各种现象的基础。例如，微生物种群可以通过允许单个细胞在多种表型之间随机转换来增强其适应性。由此产生的种群多样性确保了一些细胞能够很好地适应不可预见的环境变化。揭示这些适应性转换机制是了解不断变化的环境中微生物进化和生命的关键。最近，有人提出普恩-最初被发现是哺乳动物神经退行性疾病的原因-是真菌中更好的对冲元件，维持以促进在波动的环境中的生存。Prion蛋白可以在多种构象状态之间切换。已经证明，转换到普里子状态可以产生新的、可遗传的表型，这在许多情况下都是有益的。这个项目的首要目标是检验普里恩押注对冲假说。根据理论，套期保值元素的表型转换率会随着环境波动的速度而变化。该项目的一个中心焦点将是通过研究指定的、波动的环境选择中的Pron切换来测试这些预测。第二个重点将是使用合成生物学方法来重新设计Prion-Bit对冲设备，从而探索如何在这些元素中编码适应性特性。这些研究将需要开发新的基因工具，以及微流控平台等创新技术，以模拟复杂的环境，并以传统生物实验无法实现的方式研究细胞。这项工作将对我们对进化、发育和细胞系统的基本理解产生广泛的影响。该项目还将阐明Pron的不同作用，这些独特的元素正在微生物世界中变得常见。最后，拟议的工作将对合成生物学产生革命性的影响，使新的方案能够合理地设计一系列广泛的细胞功能。对多学科方法的关注，包括实验和理论，将为所有水平的学生提供令人兴奋的机会，为这一基本上未被探索但重要的生物学领域做出贡献。该项目的一个广泛目标是启发和培训从K-12到研究生院的学生从概念上思考量化、跨学科和工程学方法如何有助于理解生活。在将开展的具体活动中，为波士顿大学夏季挑战赛(Boston University‘s Summer Challest)开发“系统与合成生物学训练营”将对K-12教育产生影响。夏季挑战赛是一个面向高中生的寄宿暑期项目。所开发的实践活动将通过灵感大使计划被翻译给广大高中观众。在本科生层面，将扩大iGEM活动，每年将通过该项目指导几名本科生。在研究生阶段，将开发一门关于定量系统生物学的新的综合课程。最后，该项目将促进令人兴奋的技术发展，使芯片实验室系统内的生物实验微型化和自动化。将实施免费提供设备设计和操作软件的基础设施，以使这项技术广泛使用，并让学生有机会随时制作想法的原型。