The Neurotransmitter dopamine and angiogenesis

描述(由申请人提供)：血管生成是肿瘤生长超过最小尺寸所必需的，在许多其他病理生理情况下也是重要的。人们普遍预期，调节血管生成(抑制肿瘤、刺激血管功能不全)将提供重要的治疗益处。许多不同的细胞因子和生长因子表达血管生成活性，其中VPF/VEGF因其对血管内皮细胞的活性和选择性，以及在恶性肿瘤和其他临床条件下血管生成起重要作用的持续过表达而脱颖而出。最近，我们首次描述了长期用于治疗帕金森病(以及心力衰竭)的神经递质多巴胺(DA)和DA D2受体激动剂，在体内有效和选择性地阻断VPF/VEGF诱导的血管生成，无论是由肿瘤还是通过构建表达VPF/VEGF的腺病毒载体诱导的。本实验旨在研究DA或其相关化合物抑制VPF/VEGF诱导的血管生成的机制。在目标1中，我们将研究G蛋白偶联受体DAD2受体如何影响VEGFR-2信号通路。通过利用遗传学和药理学方法，Aim 2将重点揭示外周DA如何影响VPF/NEGF介导的正常和病理性血管生成。目的3研究DA及其相关分子在肿瘤腹水和实体瘤模型中作为抗血管生成因子的作用。此外，我们将研究DA或相关化合物是否可以在临床前环境中与其他常规药物(如紫杉醇)一起使用。此外，DA在其他血管生成分子介导的血管生成中的作用也将在动物模型中进行研究。将利用新生大鼠视网膜发育中的血管生成来测试DA在正常生理血管生成中的作用。综上所述，拟议的研究将得出血管生成和神经系统之间的重要概念联系，并表明已用于临床的DA可能在抗血管生成治疗中具有价值。

DESCRIPTION (provided by applicant): Angiogenesis is essential for tumor growth beyond minimal size and is important in many other pathophysiological situations. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. Very recently, we have described for the first time that the neurotransmitter dopamine (DA), which has long been used in the treatment of Parkinson's disease (as well as the treatment of cardiac failure), and DA D2 receptor agonists, potently and selectively blocks VPF/VEGF-induced angiogenesis in vivo, whether induced by tumors or by an adenoviral construct engineered to express VPF/VEGF. The experiments proposed here are designed to investigate the mechanistic details by which DA or its related compounds inhibit VPF/VEGF-induced angiogenesis. In Aim 1, we will examine how DA D2 receptor, a G-protein coupled receptor (GPCR), can influence VEGFR-2 signaling pathways. By utilizing genetic and pharmacological approaches, Aim 2 will focus to reveal how peripheral DA might affect normal and pathological angiogenesis mediated by VPF/NEGF. In Aim 3, investigation will be carried out to define the role of DA and its related molecules as anti-angiogenic agents in both tumor ascites as well as solid tumor models. Moreover, we will examine whether DA or related compounds can be employed with other conventional drugs (such as Taxol) in preclinical settings. Furthermore, the role of DA in angiogenesis mediated by other angiogenic molecules will also be investigated in animal models. Developmental angiogenesis in the retinas of newborn rats will be utilized to test the effect of DA in normal physiological angiogenesis. Taken together, the proposed studies will draw an important conceptual link between angiogenesis and the nervous system and suggest that DA, already in clinical use for other purposes, may have value in anti-angiogenesis therapy.