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.

项目总结