NDC for the Optical Control of Biological Function

说明(应用程序摘要) 我们建议创建一个用于生物功能光学控制的NDC，以开发快速打开和关闭细胞中选定蛋白质的方法。这些策略广泛适用于各种蛋白质类别。该方法将用于对单个蛋白质的生物分子动力学进行非侵入性的、定量的精确控制，以及控制蛋白质对之间的信号相互作用。这种方法可以使我们更接近生物学的中心目标之一：将分子事件，特别是细胞与器官的功能和有机体的行为直接联系起来。这些进展为药物发现、合成生物学和疾病的直接治疗带来了希望。 我们将开发三个技术平台：1)用于光学控制和化学整合到蛋白质中的模块化部件的化学和分子工具包，2)用于将可光切换的蛋白质安装到细胞中的病毒传递，以及3)使在体内解决这些纳米缺陷成为可能的光传递系统。我们将致力于解决三个工程和临床挑战：a)设计光学控制单个蛋白质的功能状态和蛋白质对或组的信号相互作用的一般策略；b)获得对体外细胞的信号和酶活性的光学控制；c)采用这些方法来治疗视网膜和心脏疾病。全国发展委员会的成员将被组织成综合的、跨学科的小组。我们预计会有三个主要结果。首先，几轮化学合成、基因工程和生物测试将有助于开发蛋白质功能的光学控制、特定的光门正交连接以及体内分子和光传递的最佳方法的基本设计。其次，我们将在人类疾病的动物模型中使用光门蛋白。第三，在5年内，我们将制定基于细胞的药物筛选和合成细胞遥控开关的应用战略，并将进行毒性评估，以指导可用于临床的生物兼容设备的开发。

DESCRIPTION (application abstract) We propose to create an NDC for the Optical Control of Biological Function, to develop methods for rapidly turning select proteins in cells on and off with light. The strategies are broadly applicable across protein classes. The approach will be used for the non-invasive, quantitatively precise, control of the biomolecular dynamics of individual proteins, and for controlling signaling interactions between pairs of proteins. This approach can bring us closer to one of the central goals in biology: that of directly relating molecular events in particular cells to the function of an organ and the behavior of the organism. The developments hold promise in medicine for drug discovery, synthetic biology and the direct treatment of disease. We will develop three technology platforms: 1) chemical and molecular toolkits of modular parts for optical control and chemical integration into proteins, 2) viral delivery for installing photo-switchable proteins into cells, and 3) light delivery systems that make it possible to address these nanodvices in vivo. We will work to solve three engineering and clinical challenges: a) devise a general strategy for optical control over the functional state of individual proteins and the signaling interactions of pairs or groups of proteins; b) gain optical control over the signaling and enzymatic activity of cells in vitro, and c) adapt these approaches to treat retinal and cardiac pathologies. Members of the NDC will be organized into integrated, interdisciplinary teams. We expect three major outcomes. First, rounds of chemical synthesis, genetic engineering and biological testing will help develop the basic design for optical control of protein function, for the specific orthogonal attachment of light-gates, and for the optimal methods of molecular and light delivery in vivo. Second, we will employ light-gated proteins in animal models of human disease. Third, over 5 years we will formulate strategies for applications to cell-based drug screening and remote control switches for synthetic cells, and we will evaluate toxicity to guide the development of biocompatible devices that could be used in the clinic.