S-Adenosylmethionine and Pneumocystis treatment

说明(申请人提供)：虽然尼古丁的药理特性并不广为人知，但它的药理特性之一是能够导致关键代谢中间体S-腺苷蛋氨酸(ADOMet)的肺部浓度降低。这种代谢产物在基因和酶调节、多胺生物合成、蛋氨酸循环和叶酸代谢中发挥重要作用。肺孢子虫是免疫抑制人群的一种重要肺部病原体，会导致肺孢子虫肺炎(PCP)，它需要ADOMet，就像所有其他细胞一样。然而，肺孢子虫的独特之处在于它能够自行合成这种化合物，并且必须从其宿主那里获得ADOMet。我们有数据表明，尼古丁在大鼠模型中治疗PCP。支持这一点的是一项对艾滋病患者进行的大型研究的临床数据，数据显示，五氯苯酚在吸烟者中复发的频率较低。目的1.研究尼古丁对PCP大鼠模型的治疗作用：寻找尼古丁与治疗PCP的主要药物甲氧苄啶/磺胺甲恶唑的协同作用。植物产生的同分异构体S-(-)和烟草烟雾产生的R-()同分异构体都将被检测到。目的2.研究尼古丁异构体对ADOMet影响的组织特异性。我们推测尼古丁治疗PCP的有效性与尼古丁对肺ADOMet的选择性作用有关。我们将检查各种动物组织中尼古丁诱导的细胞内ADOMet池的变化。目的3.研究尼古丁异构体在肺中引起ADO-Met耗竭的机制。尼古丁导致肺组织中ADOMet耗竭的机制可能是ADOMet合成减少、多胺代谢增加、甲基酶活性增加或这些因素的组合。我们假设，增加多胺代谢是最重要的，但将检查所有三种潜在的机制。目的研究尼古丁慢性染毒大鼠肺组织蛋白质表达的差异。虽然我们可以描述尼古丁影响Adobe Met的逻辑机制，但也可能涉及意想不到的机制。完成这些目标将为开发尼古丁或尼古丁类似物作为PCP的单一或辅助疗法奠定基础。

DESCRIPTION (provided by applicant): Although it is not widely known, among the pharmacological properties of nicotine is the ability to cause a reduction in lung concentration of a key metabolic intermediate, S-adenosylmethionine (AdoMet). This metabolite plays important roles in gene and enzyme regulation, polyamine biosynthesis, methionine cycling and folate metabolism. The fungus Pneumocystis, an important lung pathogen for immunosuppressed persons which causes Pneumocystis pneumonia (PCP), requires AdoMet, as do all other cells. However, Pneumocystis is unique in being able to synthesize this compound itself and must obtain AdoMet from its host. We have data showing that nicotine treats PCP in a rat model. Supporting this are clinical data from a large study of AIDS patients showing that PCP relapse is less frequent among smokers. The following Aims will be pursued: Aim 1. We will study the ability of nicotine to treat rat model of PCP: We will look for synergism using nicotine and trimethoprim/sulfamethoxazole, the primary drug for treatment of PCP. Both the epimer S-(-) produced by plants and the R-(+) epimer produced in tobacco smoke will be examined. Aim 2. We will study the tissue specificity of the effect of nicotine isomers on AdoMet. We hypothesize that the effectiveness of nicotine in treating PCP relates to the selective effect of nicotine on lung AdoMet. We will examine various animal tissues for nicotine-induced changes in the intracellular AdoMet pool. Aim 3. We will study the mechanism by which nicotine isomers induced AdoMet depletion in the lung. The mechanism underlying nicotine-induced AdoMet depletion in lung tissue could be a decrease in AdoMet synthesis, an increase in polyamine metabolism, an increase in methylase activity or a combination of these. We hypothesize that increased polyamine metabolism is most important but will examine all three potential mechanisms. Aim 4 We will study differential protein expression in lungs of rats chronically treated with nicotine. Although we can describe the logical mechanisms by which nicotine could affect AdoMet, it is possible that unanticipated mechanisms could be involved. Completion of these Aims will lay the groundwork for developing the nicotine or nicotine analogues as sole or adjunctive therapy for PCP.