S-Adenosylmethionine and Pneumocystis treatment

S-腺苷甲硫氨酸和肺孢子虫治疗

• 批准号: 6986225
• 负责人: SALIM MERALI
• 金额: $ 36.52万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986225
• 关键词: Pneumocystis; Pneumocystis carinii; Pneumocystis pneumonia; S adenosylmethionine; aminoacid metabolism; cytoprotection; drug administration routes; drug interactions; intermolecular interaction; laboratory rat; liquid chromatography mass spectrometry; matrix assisted laser desorption ionization; methylation; microorganism disease chemotherapy; nicotine; nonhuman therapy evaluation; pharmacokinetics; polyamines; proteomics; stereoisomer; sulfamethoxazole; tissue /cell culture; trimethoprim

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.

描述（由申请人提供）：尽管尼古丁的药理学特性尚未广为人知，但它能够导致关键代谢中间体 S-腺苷甲硫氨酸 (AdoMet) 的肺浓度降低。这种代谢物在基因和酶调节、多胺生物合成、蛋氨酸循环和叶酸代谢中发挥重要作用。肺孢子菌是免疫抑制者的一种重要肺部病原体，可导致肺孢子虫肺炎 (PCP)，与所有其他细胞一样，它也需要 AdoMet。然而，肺孢子虫的独特之处在于能够自行合成这种化合物，并且必须从其宿主获得 AdoMet。我们有数据显示尼古丁可以在大鼠模型中治疗 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点，该研究表明吸烟者中 PCP 复发的频率较低。 我们将追求以下目标： 目标 1. 我们将研究尼古丁治疗 PCP 大鼠模型的能力：我们将寻找尼古丁和甲氧苄啶/磺胺甲恶唑（治疗 PCP 的主要药物）的协同作用。将检查植物产生的差向异构体 S-(-) 和烟草烟雾中产生的差向异构体 R-(+)。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 库的变化。目标 3. 我们将研究尼古丁异构体诱导肺部 AdoMet 消耗的机制。 尼古丁诱导肺组织中 AdoMet 消耗的机制可能是 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，但我们将检查所有三种潜在机制。目标 4 我们将研究长期接受尼古丁治疗的大鼠肺部的差异蛋白表达。尽管我们可以描述尼古丁影响 AdoMet 的逻辑机制，但也可能涉及意想不到的机制。这些目标的完成将为开发尼古丁或尼古丁类似物作为 PCP 的单一或辅助疗法奠定基础。