Biological Chemistry of Reactive Nitrogen Species Signaling in Cancer Etiology

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著的生理和病理生理现象中发挥重要作用。尽管它非常小，但就细胞分子而言，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“双面的”，执行有害或有益的行为。是什么控制着这种矛盾的行为尚不清楚。我们建议研究一氧化氮的一个重要作用，作为一个信使分子，启动信号级联反应，导致细胞的适当反应。NO已被提出影响多种信号机制，我们选择研究NO在肿瘤发展中的作用。众所周知，一氧化氮具有促癌和抗癌的作用。我们将应用一种新的理论方法来解决这个问题，它可以做出具体的、可测试的预测。我们的研究将从简单小分子的试管化学到分离的信号蛋白，再到这些蛋白在细胞中的激活，最后是NO信号在动物肿瘤模型中的重要性。我们希望开发一种生化“路线图”，可以引导特定治疗模式的设计，以允许智能操纵体内普遍的化学条件和/或蛋白质反应，并将“促癌”生物作用转向“抗癌”。公共卫生相关性：我们将开展的研究旨在了解协调癌症发展的细胞之间的机制。我们的总体方法是试图理解由非常小的活性分子一氧化氮（NO）决定信号传导的化学过程。我们的实验系统将跨越“试管”研究，从小分子到细胞和蛋白质，最后到使用小鼠肿瘤模型的研究。我们获得的见解可能会成为开发癌症新疗法的基础。

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.