Fluorescence Sensing of NO: Development of Reversible Sensors Using Fe(III)

NO 的荧光传感：使用 Fe(III) 开发可逆传感器

基本信息

批准号：
7778248
负责人：
Michael Pluth
金额：
$ 3.08万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778248
关键词：
Active Sites Address Affinity Alzheimer&apos s Disease Amides Binding Binding Sites Biological Biological Models Biological Process Biology Cardiovascular system Cells Characteristics Chemicals Chemistry Complex Coupled Detection Development Electron Transport Electronics Electrons Environmental Pollutants Event Exhibits Family Fluorescence Fluorescent Probes Gatekeeping Goals Health Hazards Huntington Disease Hydrophobicity Image Immune In Vitro Investigation Lead Life Ligands Locales Location Medicine Methods Modeling Multiple Sclerosis Nerve Degeneration Nervous system structure Nitric Oxide Oxidation-Reduction Parkinson Disease Phase Play Production Property Regulation Research Role Scheme Signal Transduction Solutions Source Stimulus System Techniques Time Vasodilation base bioimaging biological systems carcinogenesis cellular targeting design fluorophore functional group in vivo interest nervous system disorder numb protein optical imaging prevent public health relevance response restoration scaffold sensor small molecule tumor growth

项目摘要

DESCRIPTION (provided by applicant): Nitric oxide (NO) has historically been viewed as an environmental pollutant and as an atmospheric health hazard, but recently it has been shown to play an active role in biological signaling events in the cardiovascular, immune, and nervous systems. Regulation of NO production is of immense importance because low cellular concentrations of NO are beneficial for vasodilation and immune activity such as preventing tumor growth. Overproduction of cellular NO, however, can lead to the proliferation of reactive NO species which have been implicated in carcinogenesis and several degenerative neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Although several NO sensors currently exist, they all have limitations which diminish the facility of in vivo use. While NO detection has been accomplished in vivo, the reversible sensing of NO remains an important factor in quantifying NO concentrations in different cellular locales and in response to external stimuli. This proposal involves the design of a reversible binding site for NO coupled with photoinduced electron transfer (PET) to allow for fluorescent imaging. The ultimate goal of this research is to develop a reversible fluorescent probe for cellular levels of NO which can be used in vivo for the temporal and spatial detection of NO. The proposed family of fluorescent sensors use paramagnetic Fe(lll) (S = 1/2) centers serving a dual role as both fluorescence quencher and binding site for NO. Coordination of NO to the Fe(lll) center will afford a diamagnetic {Fe-NO}6 complex, allowing for the restoration of fluorescence on the pendant fluorophore. The ligand scaffold provides a unique platform where both the ligand electronics and the hydrophobic pocket for NO binding can be finely tuned. Various ligand substitutions and fluorophores will be investigated to tune the NO binding properties of the Fe(lll) center to favor reversible NO binding; functional group incorporation into the ligand can allow for cellular targeting. PUBLIC HEALTH RELEVANCE Overproduction of cellular nitric oxide (NO) can lead to the proliferation of reactive NO species (RNOS) which have been implicated in carcinogenesis and several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. A detailed understanding of the role of NO as a chemical messenger in biological systems has implications that span across many fields of medicine. In this application, we propose the design of fluorescent probes for NO which will allow for the detection and quantification of NO in cellular components.

描述（由申请人提供）：一氧化氮（NO）历史上一直被视为一种环境污染物，也是一种大气健康危害，但最近已证明它在心血管，免疫和神经系统的生物信号事件中起着积极作用。 NO生产的调节非常重要，因为NO的低细胞浓度对血管舒张和免疫活性有益，例如预防肿瘤生长。但是，细胞NO的过量生产可能导致反应性NO物种的扩散，这些物种与癌变和几种退化性神经系统疾病有关，包括阿尔茨海默氏病，帕金森氏病，亨廷顿氏病和多发性硬化症。尽管目前没有几个传感器，但它们都有局限性减少了体内使用的设施。尽管在体内尚未实现检测，但NO的可逆感知仍然是量化不同细胞局部和对外部刺激的响应中NO浓度的重要因素。该建议涉及设计可逆的结合位点，以与光诱导的电子传递（PET）相结合，以允许荧光成像。这项研究的最终目的是开发一种可逆的荧光探针，以用于NO的细胞水平，该探针可在体内用于NO的时间和空间检测。拟议的荧光传感器家族使用顺磁性Fe（LLL）（s = 1/2）中心，既可以作为荧光淬灭剂和结合位点，又发挥了双重作用。 Fe（LLL）中心的NO配位将提供透明{Fe-no} 6复合物，从而可以恢复吊坠荧光团上的荧光。配体支架提供了一个独特的平台，可以很好地调整配体电子设备和无粘合物的疏水口袋。将研究各种配体取代和荧光团，以调整Fe（LLL）中心的无结合特性，以偏爱可逆的无结合；功能组掺入配体可以允许细胞靶向。公共卫生的相关性过量生产过量的细胞一氧化氮（NO）可能导致反应性NO物种（RNO）的扩散，这些物种（RNO）与癌变和几种神经系统疾病有关，包括阿尔茨海默氏病，帕金森病，帕金森氏病，亨廷顿氏病和多发性硬化症。对NO作为化学信使在生物系统中的作用的详细理解具有许多医学领域的含义。在此应用中，我们提出了NO荧光探针的设计，这将允许在细胞成分中检测和定量NO。