Metal Coordination Compounds as Reporters for Biological NO

金属配位化合物作为生物 NO 的报告基因

• 批准号: 1265770
• 负责人: Stephen Lippard
• 金额: $ 50万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1265770&HistoricalAwards=false
• 关键词: Metal; Coordination; Compounds; Reporters; Biological

Nitric oxide (NO) is an important molecule that controls many biological processes including smooth muscle dilation in the heart and other organs, neurotransmission, and functioning of the immune system. Through this award, funded by the Chemical Structure, Dynamics, and Mechanisms B Program of the Division of Chemistry, Professor Stephen J. Lippard from the Massachusetts Institute of Technology will investigate the chemistry of nitric oxide with transition metal complexes that can be incorporated into novel, peptide-based, platforms for its detection as a signaling agent in biology. This project investigates these roles through the preparation and application of bright, light-emitting molecules based on transition metal chemistry to track the generation and translocation of nitric oxide to its biological targets. Several of these targets include transition metals centers, and the chemistry by which they respond to NO is another subject of investigation. By directing the sensors to specific cellular locales, such as the cell membrane or organelles like the mitochondrion, spatiotemporal information about NO as a signal transduction molecule can be obtained by fluorescence microscopic studies. Reactive species derived from NO, specifically HNO (nitroxyl) and HSNO (nitrosothiol), will also be investigated. Through chemistry, the probes will be made selective for NO, HNO, or HSNO, kinetically tuned for rapid turn-on, ratiometric to allow for quantitation, reversible, and able to emit at low energies to minimize unwanted background. The chemical dynamics and mechanisms discovered during the design and implementation of the sensors may have parallels in living systems and thereby enrich our knowledge of how transition metal centers respond to nitric oxide and its derivatives. Peptides provide an excellent platform for incorporating units to localize the sensors to subcellular locales, a great advantage for studying functions in live cells and tissue slices. Applications ranging from the design of antibiotics to the determination of the roles of nitric oxide in sensory perception can be envisioned. These projects will continue the training of young scientists in chemistry. Graduate and postdoctoral researchers on the project are also mentors to undergraduate research opportunity participants (UROPs) at MIT. These scientists are encouraged to communicate their work both orally and in writing. Many subsequently assume key positions in academic or industrial organizations and some are active in outreach programs at schools in the local communities.

一氧化氮（NO）是控制许多生物过程的重要分子，包括心脏和其他器官的平滑肌扩张、神经传递和免疫系统功能。麻省理工学院的Stephen J. Lippard教授将通过这项由化学系化学结构、动力学和机制B项目资助的奖项，研究具有过渡金属配合物的一氧化氮的化学性质，过渡金属配合物可以结合到新的、基于肽的平台中，作为生物学中的信号剂进行检测。本项目通过基于过渡金属化学的明亮发光分子的制备和应用来研究这些作用，以跟踪一氧化氮的生成和向其生物靶标的易位。其中一些目标包括过渡金属中心，它们对NO反应的化学反应是另一个研究课题。通过将传感器定向到特定的细胞位置，如细胞膜或细胞器（如线粒体），可以通过荧光显微镜研究获得NO作为信号转导分子的时空信息。由NO衍生的活性物质，特别是HNO（硝基）和HSNO（亚硝基）也将被研究。通过化学，探针将被制造为选择性NO， HNO或HSNO，动力学调整为快速开启，比率调整为定量，可逆，并且能够以低能量发射以减少不必要的背景。在设计和实现传感器过程中发现的化学动力学和机制可能在生命系统中有相似之处，从而丰富了我们对过渡金属中心如何响应一氧化氮及其衍生物的知识。多肽提供了一个很好的平台，可以结合单元将传感器定位到亚细胞区域，这对于研究活细胞和组织切片的功能具有很大的优势。应用范围从抗生素的设计到确定一氧化氮在感官知觉中的作用可以设想。这些项目将继续培养年轻的化学科学家。该项目的研究生和博士后研究人员也是麻省理工学院本科生研究机会参与者（urop）的导师。鼓励这些科学家以口头和书面形式交流他们的工作。许多人随后在学术或工业组织中担任重要职位，有些人积极参与当地社区学校的外展项目。