The Neurotransmitter Dopamine and Gastric Cancer

描述（由申请人提供）：本申请的长期目标是研究多巴胺（DA）在胃癌发病和治疗中的作用。最近，我们证明了在人胃癌组织中完全缺乏内源性DA，并且外源性DA治疗延缓了非转移性人胃癌异种移植物的生长。也有报道表明，低剂量的DA抑制活性氧（ROS）的产生。此外，由于ROS在胃癌的诱导中起着重要作用，我们假设DA可能通过调节胃组织中ROS的产生来控制胃肿瘤的发生。本实验旨在探讨胃内源性DA的状态及其与胃肿瘤发生过程中ROS产生的关系，以及DA调节胃组织中ROS产生的分子途径。最后，我们还将研究DA在高转移性胃癌临床前模型中单独使用或与常规化疗药物联合使用的可能性。目的一：探讨内源性胃多巴胺在胃肿瘤发生中的作用。实验设计：检测野生型和DA受体敲除的猫幽门螺杆菌接种小鼠胃组织中ROS、内源性胃DA和酪氨酸羟化酶（DA合成的限制性酶）的状态。目的二世。探讨多巴胺介导的胃癌抑制的分子机制。实验设计：阐明DA抑制胃上皮细胞ROS的信号通路。第三目标。探讨DA在转移性胃癌中的作用。实验设计：将在高度转移的人胃癌原位异种移植物中单独或与常规抗癌药物联合进行效果测试。从这项研究中获得的知识对于深入了解胃癌的发病机制，识别高风险个体，以及开发新的治疗方法来对抗晚期胃癌（美国大多数胃癌患者处于晚期临床阶段）具有重要意义，目前尚无有效的治疗方法。

DESCRIPTION (provided by applicant): The long- term objective of this application is to investigate the role of dopamine (DA) in the pathogenesis and treatment of gastric cancer. Very recently, we demonstrated that there is a complete absence of endogenous DA in human gastric cancer tissues and that treatment with exogenous DA retards the growth of a non- metastatic human gastric cancer xenograft. There are also reports indicating that low doses of DA inhibit the production of reactive oxygen species (ROS). Furthermore, because ROS play an important role in the induction of gastric cancer, we hypothesized that DA could control gastric tumorigenesis by regulating ROS production in gastric tissues. The experiments proposed here are designed to investigate the status of endogenous stomach DA, its relationship with ROS produced during gastric tumorigenesis, and the molecular pathways by which DA regulates ROS production in gastric tissues. Finally, we will also examine the possibility that DA might be utilized alone or in combination with conventional chemotherapeutic drugs in a highly metastatic gastric cancer preclinical model. Aim I. To determine the role of endogenous stomach dopamine in gastric tumorigenesis. Experimental Design: The status of ROS, endogenous stomach DA and tyrosine hydroxylase , the rate limiting enzyme for DA synthesis will be examined in gastric tissues collected from wild type and DA receptor knock-out Helicobacter felis (H.felis) - inoculated mice. Aim II. To elucidate the molecular mechanism of dopamine mediated inhibition of gastric cancer. Experimental Design: The signaling pathways through which DA inhibits ROS in gastric epithelial cells will be elucidated. Aim III. To investigate the effect of DA in metastatic gastric cancer. Experimental Design: The effect of will be tested either alone or in combination with conventional anticancer drugs in a highly metastatic orthotopic human gastric cancer xenograft. The knowledge generated from this study will be important to gain insight into the pathogenesis of gastric cancer, identify high risk individuals, and develop newer therapies to combat advanced gastric cancer (majority of gastric cancer patients in the United States are seen in an advanced clinical stage), which, as of yet, has no significant treatment.