BIOLOGY OF SPATIOTEMPORAL NITRIC OXIDE GRADIENTS

时空一氧化氮梯度的生物学

• 批准号: 6263271
• 负责人: Scott S Bohle
• 金额: $ 156.15万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263271
• 关键词: nitric oxide

The central tenet to be investigated in this proposal is that nitric oxide (NO) is a cell signaling molecule and mediator of cytotoxicity is not just dependent upon its instantaneous concentration at a given point, but rather it is also dependent upon its concentration gradient. The protocols that are currently in use for NO research do not allow the spatial release of biologically relevant concentration gradients of NO, nor do they allow the direct temporal and spatial detection of NO with fine resolution. An important goal of this proposal is to develop novel fluorescent probes and donors that afford spatiotemporal detection of NO, and to develop new methods for well defined spatiotemporal release of NO. To achieve a greater understanding of the role of NO gradients in mediating cell signaling and cytotoxicity, the research conducted in this COBRE IDeA proposal will vertically integrate five medically relevant research projects that employ unique but complementary experimental systems. These novel NO reagents will be used throughout this proposal and will be specifically used in this project to test the hypothesis that nitric oxide is a sperm chemotactic molecule. Because NO has been implicated in bowel dysfunction in the elderly, Project 2 will employ an aged rat model system to investigate whether alterations in neural and gastrointestinal NO signaling within the enteric nervous system of the bowel investigate whether alterations in neural and gastrointestinal NO signaling within the enteric nervous system of the bowel are involved. Project 3 will elucidate specific cell physiology, pathology, and signaling pathways involving NO production in the upper airway epithelium and its role in exacerbating and/or moderating disease caused by respiratory tract pathogens. Project 4 will investigate the role of NO in retrovirus-induced neurodegeneration using a murine retrovirus model. This investigation will provide insight into the potential role of NO in HV-induced neurological disease. Finally, Project 5 will examine the role of NO in controlling infection by obligate intracellular bacterial human pathogens. The bacterial response to NO stress will also be investigated. Not only will these studies lead to the development of novel NO release and detection reagents with broad scale applicability, they will also provide a greater understanding of the role of NO as a signaling molecule, and as protective or damaging factor in the progression of human disease.

该提案要研究的中心原则是一氧化氮（NO）是一种细胞信号分子和细胞毒性介质不仅取决于其在给定点的瞬时浓度，而且还取决于其浓度梯度。目前用于 NO 研究的方案不允许在空间上释放生物学相关的 NO 浓度梯度，也不允许以高分辨率直接在时间和空间上检测 NO。该提案的一个重要目标是开发能够进行 NO 时空检测的新型荧光探针和供体，并开发明确 NO 时空释放的新方法。为了更好地了解 NO 梯度在介导细胞信号传导和细胞毒性中的作用，COBRE IDeA 提案中进行的研究将垂直整合五个医学相关的研究项目，这些项目采用独特但互补的实验系统。这些新颖的一氧化氮试剂将在整个提案中使用，并将专门用于该项目，以测试一氧化氮是精子趋化分子的假设。由于NO与老年人的肠道功能障碍有关，项目2将采用老年大鼠模型系统来研究肠道肠神经系统内神经和胃肠道NO信号传导的改变是否涉及肠道神经和胃肠道NO信号传导的改变。项目3将阐明涉及上气道上皮中NO产生的特定细胞生理学、病理学和信号传导途径及其在加剧和/或减轻呼吸道病原体引起的疾病中的作用。项目 4 将使用鼠逆转录病毒模型研究 NO 在逆转录病毒诱导的神经变性中的作用。这项研究将深入了解一氧化氮在高压诱发的神经系统疾病中的潜在作用。最后，项目 5 将研究 NO 在控制专性细胞内细菌人类病原体感染中的作用。细菌对 NO 胁迫的反应也将被研究。这些研究不仅将导致开发出具有广泛适用性的新型 NO 释放和检测试剂，还将让人们更好地了解 NO 作为信号分子以及作为人类疾病进展中的保护或破坏因子的作用。