S-Adenosylmethionine and Pneumocystis treatment

性状（由申请方提供）：尽管尚未广为人知，但尼古丁的药理学特性之一是能够导致关键代谢中间体S-腺苷甲硫氨酸（S-腺苷甲硫氨酸）的肺浓度降低。这种代谢产物在基因和酶的调节、多胺的生物合成、蛋氨酸循环和叶酸代谢中起重要作用。真菌肺孢子虫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，它需要蛋氨酸。然而，肺孢子虫的独特之处在于能够自己合成这种化合物，并且必须从其宿主中获得甲硫氨酸。我们有数据显示尼古丁可以治疗大鼠模型中的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，该数据显示，吸烟者中PCP复发的频率较低。 将追求以下目标：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。植物产生的差向异构体S-（-）和烟草烟雾中产生的R-（+）差向异构体都将被检测。目标2.我们将研究尼古丁异构体对尼古丁代谢的影响的组织特异性。我们假设尼古丁治疗PCP的有效性与尼古丁对肺组织Met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谷氨酸盐池的变化。目标3：我们将研究尼古丁异构体诱导肺中C3 Met耗竭的机制。 尼古丁诱导的肺组织中C3 Met耗竭的潜在机制可能是C3 Met合成减少、多胺代谢增加、甲基化酶活性增加或这些的组合。 我们假设多胺代谢增加是最重要的，但将检查所有三个潜在的机制。目的4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可能影响尼古丁的逻辑机制，但可能涉及意料之外的机制。这些目标的完成将为开发尼古丁或尼古丁类似物作为PCP的唯一或替代疗法奠定基础。

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.