Biological Chemistry of Reactive Nitrogen Species Signaling in Cancer Etiology

癌症病因学中活性氮信号传导的生物化学

• 批准号: 8024524
• 负责人: Jack R Lancaster
• 金额: $ 29.64万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-27 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024524
• 关键词: Affect; Anchorage-Independent Growth; Animals; Behavior; Biochemical; Biochemistry; Biodiversity; Biological; Biological Models; Cancer Etiology; Cancerous; Cells; Chemicals; Chemistry; Cysteine; Data; Development; Environment; Exposure to; Health; Immune; In Vitro; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Mediating; Modality; Modeling; Modification; Monomeric GTP-Binding Proteins; Mus; Nature; Neoplasm Metastasis; Nitric Oxide; Nitrogen Oxides; Nitrosation; Outcome; Oxidants; Pattern; Phenotype; Physiological; Play; Post-Translational Protein Processing; Process; Property; Proteins; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Role; S-nitro-N-acetylpenicillamine; Signal Transduction; Signaling Protein; Stress; Sulfhydryl Compounds; System; Testing; Therapeutic; Tube; Tumorigenicity; Work; base; cancer therapy; chemical kinetics; clinically relevant; cytotoxic; design; in vivo; insight; neoplastic cell; oxidation; protein activation; response; small molecule; tumor; tumor progression

DESCRIPTION (provided by applicant): Nitric oxide (NO) is one of the smallest molecules in Nature and has recently been discovered to play important roles in a remarkable array of physiological and pathophysiological phenomena. In spite of the fact that it is extremely small, as cellular molecules go, its actions are multiple and not well understood. In many cases, its actions are "Janus-faced", performing either harmful or helpful actions. What controls this contradictory behavior is unknown. We propose to study one important role of NO, as a messenger molecule that initiates signaling cascades resulting in appropriate responses of the cell. NO has been proposed to effect a variety of signaling mechanisms, and we have chosen to examine the roles of NO in tumor development. NO is well- known to possess pro-cancerous and also anti-cancerous actions. We will apply a new theoretical approach to this problem, which makes specific and testable predictions. Our studies will range from test-tube chemistry of simple small molecules to isolated signaling proteins to the activation of these proteins in cells and finally the importance of NO signaling in an animal tumor model. We hope to develop a biochemical "road map" that could navigate design of specific therapeutic modalities to allow intelligent manipulation of prevailing in vivo chemical conditions and/or protein responses and effect redirection of the "pro-cancerous" biological actions toward the "anti- cancerous". PUBLIC HEALTH RELEVANCE: The research we will carry out is directed to understand the mechanisms between cells that orchestrate the development of Cancer. Our overall approach is to try to understand the chemistry that determines signaling by the very small and reactive molecule nitric oxide (NO). Our experimental systems will span "test-tube" studies with small molecules to cells and proteins and finally to studies using a tumor model in mice. Insights we obtain may form the basis for the development of new therapies for cancer.

描述（由申请人提供）：一氧化氮（NO）是自然界中最小的分子之一，最近被发现在一系列显着的生理和病理生理现象中发挥着重要作用。尽管它非常小，但随着细胞分子的发展，它的作用是多种多样的，而且还没有被很好地理解。在许多情况下，它的行为是“两面性”的，要么执行有害的操作，要么执行有益的操作。是什么控制着这种矛盾的行为尚不清楚。我们建议研究 NO 的一个重要作用，它作为一种信使分子，启动信号级联反应，导致细胞做出适当的反应。 NO 已被认为可以影响多种信号传导机制，我们选择研究 NO 在肿瘤发展中的作用。众所周知，NO 具有促癌和抗癌作用。我们将应用一种新的理论方法来解决这个问题，从而做出具体且可测试的预测。我们的研究范围从简单小分子的试管化学到分离的信号蛋白，再到细胞中这些蛋白的激活，最后是动物肿瘤模型中 NO 信号传导的重要性。我们希望开发一个生化“路线图”，可以指导特定治疗方式的设计，以允许智能操纵体内普遍的化学条件和/或蛋白质反应，并有效地将“促癌”生物作用转向“抗癌”。癌变”。公共健康相关性：我们将进行的研究旨在了解协调癌症发展的细胞之间的机制。我们的总体方法是尝试了解由非常小的反应性分子一氧化氮 (NO) 决定信号传导的化学过程。我们的实验系统将涵盖小分子、细胞和蛋白质的“试管”研究，最后到使用小鼠肿瘤模型的研究。我们获得的见解可能构成开发癌症新疗法的基础。