S-Adenosylmethionine and Pneumocystis treatment

S-腺苷甲硫氨酸和肺孢子虫治疗

基本信息

批准号：
7532766
负责人：
SALIM MERALI
金额：
$ 34.25万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2010-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7532766
关键词：
Acquired Immunodeficiency Syndrome Aerosols Affect Amoeba genus Anabolism Animal Model Bacteria Biochemical Biological Cavia Cell physiology Cells Charge Clinical Data Clinical Research Cultured Cells DNA Methylation DNA biosynthesis Data Diagnostic Procedure Dose Effectiveness Enzyme Gene Failure Future Gene Expression Goals Human Infusion procedures Investigation Isomerism Laboratories Lipids Lung Malignant Neoplasms Measurement Measures Membrane Metabolic Metabolism Methionine Methylation Methyltransferase Modeling Nicotine Nucleotide Biosynthesis Organism Patients Persons Pharmaceutical Preparations Plants Plasma Play Pneumocystis Pneumocystis carinii Pneumocystis carinii Pneumonia Polyamines Probability Production Property Prophylactic treatment Proteomics Rattus Reaction Regulation Regulator Genes Relapse Research Personnel Rickettsia Role Route S-Adenosylmethionine Smoker Smoking Specificity Stereoisomer Structure of parenchyma of lung Subcutaneous Injections Techniques Testing Tissues Tobacco smoke Trimethoprim-Sulfamethoxazole Withholding Treatment Work analog animal tissue base dosage folic acid metabolism fungus immunosuppressed improved meetings minimally invasive pathogen programs protein expression quorum sensing research study response synergism therapeutic development tool

项目摘要

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在尼古丁的药理特性中虽然尚不清楚，但能够引起关键代谢中间体S-腺苷甲硫氨酸（ADOMEN）肺部浓度降低的能力。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起重要作用。真菌性肺炎藻，是免疫抑制人的重要肺病原体，会引起肺炎肺炎肺炎（PCP），需要ADOMET，所有其他细胞也需要ADOMET。但是，肺结压藻在能够合成该化合物本身并必须从其宿主那里获得ADOMET是独一无二的。我们有数据表明尼古丁在大鼠模型中处理PCP。支持这一点的是一项大量艾滋病患者的临床数据，表明吸烟者中PCP复发的频率较小。将追求以下目的：目标1。我们将研究尼古丁治疗大鼠PCP模型的能力：我们将使用尼古丁和甲氧苄啶/磺胺甲氧唑，这是PCP治疗的主要药物。将检查由植物产生的分子S-（ - ）和在烟草烟雾中产生的R-（+）异构体。 AIM 2。我们将研究尼古丁异构体对ADOMEM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ADOMET的选择性作用有关。我们将检查各种动物组织，以实现尼古丁诱导的细胞内ADOMET池的变化。 AIM 3。我们将研究尼古丁异构体在肺中诱导的ADOMET耗竭的机制。肺组织中尼古丁诱导的ADOMET耗竭的基础机制可能会降低ADOMET合成，多胺代谢的增加，甲基化酶活性的增加或它们的组合。我们假设增加的多胺代谢是最重要的，但将检查所有三种潜在的机制。 AIM 4我们将研究用尼古丁慢性治疗的大鼠肺中的差异蛋白表达。尽管我们可以描述尼古丁可能影响ADOMET的逻辑机制，但可能涉及意外机制。这些目标的完成将为开发尼古丁或尼古丁类似物作为PCP的唯一或辅助疗法奠定基础。