Chemical Probes for Imaging Reactive Sulfur, Oxygen, and Nitrogen Species in Living Cells and Clinical Samples

用于对活细胞和临床样品中的活性硫、氧和氮形态进行成像的化学探针

• 批准号: 9022649
• 负责人: Alexander Ryan Lippert
• 金额: $ 33.34万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022649
• 关键词: Address; Adrenal Cortex Hormones; Aging; Area; Asthma; Benchmarking; Biochemistry; Biocompatible; Biological Markers; Biology; Cancer Model; Cardiovascular Diseases; Cell Culture Techniques; Cell model; Cells; Cellular Phone; Cellular biology; Chemicals; Chemiluminescence assay; Chemistry; Chronic Obstructive Airway Disease; Clinical; Clinical Psychology; Clinical Research; Complex; Detection; Development; Devices; Diabetes Mellitus; Diagnostic; Disease; Disease Management; Disease Progression; Disease model; Engineering; Exhalation; Family; Fluorescence; Fluorescence Microscopy; Fluorescent Dyes; Foundations; Future; HDAC2 gene; Health; Histone Deacetylase; Home environment; Human; Human Pathology; Hydrogen Peroxide; Hydrogen Sulfide; Image; Imagery; In Vitro; Life; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Mediator of activation protein; Methods; Modality; Modeling; Molecular; Molecular Biology; Molecular Probes; Monitor; Nerve Degeneration; Nitric Oxide; Nitric Oxide Pathway; Nitrogen; Nitrogen Dioxide; Nuclear Magnetic Resonance; Optical Methods; Optics; Organic Chemistry; Organism; Oxygen; Participant; Peroxonitrite; Physiological; Physiological Processes; Physiology; Play; Production; Prognostic Marker; Proteins; Reaction; Reagent; Research; Research Personnel; Resistance; Resolution; Role; Saliva; Sampling; Signal Transduction; Signaling Molecule; Staging; Sulfur; Supporting Cell; Synthesis Chemistry; Techniques; Technology; Time; Translating; airway inflammation; asthmatic patient; base; complex biological systems; cost; design; frontier; high throughput analysis; imaging probe; infancy; innovation; insight; interest; nitration; nitroxyl; novel; oxidation; point of care; point-of-care diagnostics; respiratory; respiratory health; response; scaffold; small molecule; spatiotemporal; technology development; tool

 DESCRIPTION (provided by applicant): Reactive sulfur, oxygen, and nitrogen (RSON) species are endogenous small molecules that play fundamental roles in cellular signaling and are misregulated in diseases ranging from cancer to neurodegeneration to diabetes. This super-family of signaling molecules includes nitric oxide, hydrogen sulfide, hydrogen peroxide, and many others. Despite being involved in nearly all physiological processes, our understanding of their complex and intertwined roles remains in its infancy due, in large part, to a lack of methods to monitor these transient species in living cells and human clinical samples. This project aims to use highly innovative chemistry to develop responsive fluorescent dyes for the precise real-time tracking of specific RSON species, including hydrogen sulfide, peroxynitrite, and nitroxyl, and to use these probes to investigate their production in cellular models of lung cancer and in human saliva/exhaled breath condensates. Specifically, we aim to: 1. Develop reaction-based probes to detect and image RSON species in cells and clinical samples. There is a lack of biologically compatible methods for the detection of certain RSON species, particularly hydrogen sulfide, peroxynitrite, and nitroxyl. Leveraging our expertise in synthetic organic chemistry, we will bridge this gap by inventing new reaction-based probes to detect and image these species using fluorescence, chemiluminescence, and nuclear magnetic resonance techniques. 2. Investigate the role of RSON species in cellular models of disease. Although the ubiquitous signaling molecule nitric oxide has been well studied in cancer models, the production and roles of other RSON species remain incompletely understood. We will use newly developed and state-of-the-art reaction-based probes to characterize the complex cellular chemistry of RSON species in a cellular model of airway inflammation. 3. Develop and validate point-of-care diagnostics for the detection and management of disease. RSON chemistry has the potential to be a powerful diagnostic and prognostic marker. Indeed, exhaled nitric oxide and H2O2 are established biomarker for monitoring asthma and other respiratory ailments, but home and point-of-care monitoring remains a significant obstacle. We will develop innovative point-of-care smartphone-based RSON detection techniques for monitoring the levels of these species in the saliva and exhaled breath condensates.

 描述（由申请人提供）：活性硫、氧和氮（RSON）物质是内源性小分子，在细胞信号传导中发挥重要作用，在癌症、神经变性和糖尿病等疾病中受到错误调节。这个信号分子超家族包括一氧化氮、硫化氢、过氧化氢和许多其他分子。尽管参与了几乎所有的生理过程，但我们对它们复杂和相互交织的作用的理解仍处于起步阶段，这在很大程度上是由于缺乏方法 以监测活细胞和人类临床样品中的这些瞬时物质。该项目旨在使用高度创新的化学方法开发响应性荧光染料，用于精确实时跟踪特定的RSON物种，包括硫化氢，过氧亚硝酸盐和硝酰基，并使用这些探针来研究它们在肺癌细胞模型和人类唾液/呼出气冷凝物中的生产。具体而言，我们的目标是：1。开发基于反应的探针，以检测细胞和临床样本中的RSON物质并对其进行成像。 缺乏生物相容的方法来检测某些RSON物质，特别是硫化氢，过氧亚硝酸盐和硝酰基。利用我们在合成有机化学方面的专业知识，我们将通过发明新的基于反应的探针来弥合这一差距，以使用荧光，化学发光和核磁共振技术检测和成像这些物种。 2.研究RSON种类在疾病细胞模型中的作用。虽然普遍存在的信号分子一氧化氮已经在癌症模型中得到了很好的研究，但其他RSON种类的产生和作用仍然不完全清楚。我们将使用新开发的和最先进的基于反应的探针来表征气道炎症细胞模型中RSON物种的复杂细胞化学。 3.开发和验证用于疾病检测和管理的护理点诊断。 RSON化学具有成为强有力的诊断和预后标记物的潜力。事实上，呼出的一氧化氮和H2 O2是监测哮喘和其他呼吸系统疾病的既定生物标志物，但家庭和即时监测仍然是一个重大障碍。我们将开发创新的基于智能手机的护理点RSON检测技术，用于监测唾液和呼出气体冷凝物中这些物质的水平。