Bioorthogonal temporospatial tools

生物正交时空工具

• 批准号: 10711005
• 负责人: Jonathan Carlson
• 金额: $ 41.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711005
• 关键词: 3-Dimensional; Acceleration; Architecture; Biological; Biotechnology; Cells; Chemicals; Chemistry; Detection; Development; Epigenetic Process; Event; Gene Expression; Generations; Goals; Grain; Hybrids; Individual; Investigation; Kinetics; Ligation; Memory; Methods; Molecular; Nucleic Acid Hybridization; Nucleic Acids; Organism; Performance; Population; Property; Reaction; Recording of previous events; Research; Signal Transduction; Specificity; Speed; Synapses; System; Time; Tissues; Translating; Translations; Visualization; biomaterial compatibility; detection sensitivity; in vivo; molecular dynamics; multiplexed imaging; response; scaffold; success; tool

PROJECT SUMMARY Living systems choreograph molecular events with precise control—place, time, kinetics, and intensity —and record memories of those occurrences in synaptic networks, gene expression, epigenetic marks, and myriad other circuits that govern the where&when of biologic responses. Visualizing this choreography and tracing these histories are tasks that chemists and biologists can accomplish with only partial accuracy, considerable effort, and limited temporal range. Our research agendas are thus focused on constructing new chemical tools for temporospatial analysis of living systems, and organized around the emergent properties that result from deploying next-level bioorthogonal chemistries within multi-layered (bio)molecular architectures. The resulting hybrid systems circumvent perennial challenges, achieving: i) simultaneous speed/stability, for efficient real-time molecular machinery and longitudinal performance in vivo; ii) sensitivity for detection of rare/unique events; and iii) specificity/multiplicity, for accurate detection and fine-grained molecular encoding of (sub)cellular histories across time. Building on the momentum of ongoing mechanistic investigations and the success of our recent effort to achieve multiplexed imaging of living cells and tissues, our goals for the next five years extend bioorthogonal chemistry in applications that exploit two/three dimensional topologies, rather than singular ligation/cleavage events, and in architectures that leverage nucleic acid hybridization to encode sequence recognition, accelerate reaction kinetics, and enable signal amplification. In one set of projects, we aim to create self-amplifying programmable bioorthogonal reactions, elaborate the capabilities of this new toolkit, and apply them to transform our methods for visualizing living cells and tissues. In another, we have envisioned sequence-generating architectures that convert biocompatible chemical reactivity into amplifiable biological information, establishing the concepts of bioorthogonal translation and sequegenicity. With scaffolds that readily integrate into the workflows of existing high- performance nucleic acid biotechnologies, we anticipate broad applicability and rapid downstream development of a new generation of tools for tracking (bio)molecules, individual cells, and populations.

项目摘要 生活系统编舞分子事件具有精确控制 - 地点，时间，动力学和强度 - 并记录突触网络中这些发生的记忆，基因表达，表观遗传 标记和其他循环，这些电路都可以看到生物响应的位置 编排和追踪这些历史是化学家和生物学家可以完成的任务 因此，我们的研究议程很大，有限的时间范围。 专注于构建新的化学工具，用于暂时的生活系统和系统 由部署下一级生物串管造成的新兴特性组织 多层（BIO）分子体系结构中的化学作用。 多年生挑战，实现：i）同时速度/稳定性，用于有效的实时分子 体内的机械和纵向性能； iii）特定的/乘法，以进行准确的探测和细粒度的分子区域 跨时间的历史。 基于超级机制投资的势头和我们最近的收益的成功 为了实现活细胞和组织的多路复用成像，我们的下一个目标目标 在利用两个/树尺寸拓扑的应用中的生物正交化学，而不是 奇异的连接/切割事件，以及在利用核酸化的体系结构中 编码序列识别，加速反应动力学和启用信号放大 在项目中，我们旨在创建自我膨胀的可编程生物反应反应，详细说明您 这个新工具包的能力，并将它们转变为可视化活细胞的方法和 组织。 化学反应性对可扩增的生物信息，建立生物正交的概念 sca of sca o ofers的翻译和销售 性能核酸生物技术，我们预计适用性广泛和下游快速 开发新一代的跟踪工具（BIO）分子，单个细胞和人群。