Exploring the RNA syntax for engineering therapeutic RNA-based nano-factories

探索用于工程治疗性 RNA 纳米工厂的 RNA 语法

• 批准号: 7614502
• 负责人: LUC JAEGER
• 金额: $ 27.95万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614502
• 关键词: Antisense RNA; Architecture; Base Sequence; Biochemical; Biology; Cancerous; Catalytic RNA; Cells; Complex; Cryoelectron Microscopy; Cues; Development; Engineering; Environment; Future; Gene Expression; Goals; Immobilization; Lead; Medicine; Methods; Molecular; Muscle Rigidity; Nanostructures; Nucleic Acids; Nucleic acid sequencing; Population; Process; Property; RNA; RNA Folding; Recurrence; Research; Rest; Roentgen Rays; Solutions; Stimulus; Therapeutic; Therapeutic Agents; Time; Viral; Work; aptamer; base; chemical stability; design; disease diagnosis; engineering design; in vivo; insight; interest; locked nucleic acid; molecular assembly/self assembly; molecular shape; nano; nanodevice; nanomachine; nanoparticle; nanostructured; nanotherapeutic; nucleic acid analog; programs; response; self assembly; syntax; three dimensional structure; tool

DESCRIPTION (provided by applicant): Therapeutic agents such as small interfering siRNAs, ribozymes, and anti-sense RNAs show significant potential in new molecular approaches to down-regulate specific gene expression in cancerous or viral- infected cells. The development of safe, efficient, specific and non-pathogenic nano-particles for the packaging and delivery of multifunctional therapeutic RNAs is thus highly desirable. While programmable RNA self-assembly has been shown to potentially provide a solution towards that goal, the underlying principles for the design and engineering of multifunctional nano-structures based on RNA have still to be delineated. The long-term goal of this proposal is to contribute to the development of fully controllable and versatile bio-materials based on RNA and nucleic acid analogs for use in the study of biology, disease diagnosis, or therapy. In order to achieve this challenge, this project aims at generating stimuli-responsive programmable three-dimensional (3D) supra-molecular assemblies with control over their geometry, topology, directionality and addressability and able to respond to the cues of the environment. For instance, programmable, addressable and multifunctional 3D nano-cages that allow precise immobilization in 3D space of various functional therapeutic modules with catalytic or recognition properties will be synthesized and characterized by biochemical and biophysical methods such as AFM and cryo electron microscopy. Some of these RNA nano-devices will be engineered to switch reversibly between distinct supra-molecular shapes in response to small target compounds. The principles underlying the engineering of concerted and transient, time-activated complex functions as well as the enhancement of the chemical stability of these assemblies using RNA structural mimics like locked-in nucleic acid (LNA) will be investigated. This work will provide new insights in the control of self-assembly processes involving large population of RNA molecules and will pave the way towards the design of complex RNA-based nano-machines with strong potential in biology and medicine. It is anticipated that this project will establish the fundamental assembly and functional principles for the design and development of versatile responsive vehicles for therapeutic RNAs that will be suitable for in vivo applications and amenable to industrial-scale development in the future.

描述（由申请人提供）：治疗剂如小干扰siRNA、核酶和反义RNA在新的分子方法中显示出下调癌细胞或病毒感染细胞中特定基因表达的显著潜力。因此，高度期望开发用于包装和递送多功能治疗性RNA的安全、有效、特异性和非致病性纳米颗粒。虽然可编程RNA自组装已被证明有可能为实现这一目标提供解决方案，但基于RNA的多功能纳米结构的设计和工程化的基本原理仍有待描述。该提案的长期目标是促进基于RNA和核酸类似物的完全可控和通用生物材料的开发，用于生物学研究，疾病诊断或治疗。为了实现这一挑战，该项目旨在生成刺激响应可编程三维（3D）超分子组件，控制其几何形状，拓扑结构，方向性和可寻址性，并能够响应环境的提示。例如，可编程的、可寻址的和多功能的3D纳米笼，其允许在3D空间中精确固定具有催化或识别性质的各种功能性治疗模块，将通过生物化学和生物物理方法如AFM和冷冻电子显微镜来合成和表征。这些RNA纳米器件中的一些将被设计成响应于小的目标化合物而在不同的超分子形状之间可逆地切换。协调和瞬时的，时间激活的复杂功能的工程以及使用RNA结构模拟物，如锁定核酸（LNA）的化学稳定性的增强的基本原则将被调查。这项工作将为涉及大量RNA分子的自组装过程的控制提供新的见解，并将为设计在生物学和医学方面具有强大潜力的复杂的基于RNA的纳米机器铺平道路。预计该项目将为设计和开发适用于体内应用并适合未来工业规模开发的治疗性RNA的通用响应载体建立基本组装和功能原理。