S-Adenosylmethionine and Pneumocystis treatment

描述（由申请人提供）：尽管不广为人知，尼古丁的药理学特性之一是能够导致肺中关键代谢中间体s -腺苷蛋氨酸（AdoMet）浓度的降低。该代谢物在基因和酶调控、多胺生物合成、蛋氨酸循环和叶酸代谢中发挥重要作用。肺囊虫真菌是免疫抑制者的一种重要肺部病原体，可引起肺囊虫性肺炎（PCP），它和所有其他细胞一样需要AdoMet。然而，肺囊虫是独特的，能够自己合成这种化合物，必须从其宿主获得AdoMet。我们有数据显示尼古丁在大鼠模型中治疗PCP。一项针对艾滋病患者的大型研究的临床数据支持了这一观点，该研究表明，吸烟人群中PCP复发的频率较低。将实现以下目标：目标1。我们将研究尼古丁治疗PCP大鼠模型的能力：我们将寻找尼古丁与治疗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S-(-)外显体和烟草烟雾产生的R-(+)外显体都将被检查。目标2。我们将研究尼古丁异构体对AdoMet影响的组织特异性。我们假设尼古丁治疗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。目标3。我们将研究尼古丁异构体诱导AdoMet在肺部耗竭的机制。尼古丁诱导肺组织AdoMet耗竭的机制可能是AdoMet合成减少、多胺代谢增加、甲基化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，但将检查所有三个潜在的机制。目的4：我们将研究尼古丁长期治疗大鼠肺中的差异蛋白表达。虽然我们可以描述尼古丁影响AdoMet的逻辑机制，但也有可能涉及到意想不到的机制。这些目标的完成将为开发尼古丁或尼古丁类似物作为PCP的单独或辅助治疗奠定基础。

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.