PNEUMOCYSTIS CARINII POLYAMINE METABOLISM

描述：（改编自申请人摘要）。 卡氏肺孢子虫 肺炎（PCP）影响超过50%的艾滋病患者。 DL-α-二氟甲基鸟氨酸（DFMO，依氟鸟氨酸），一种 多胺生物合成的关键酶，已被用作替代物 治疗PCP。 虽然DFMO比大多数PCP疗法毒性小， 疗效也较低，因此目前不认为它是一种治疗方法 治疗这种疾病 本实验室开发了新工具， 卡氏肺孢子虫的研究和多胺代谢的研究。 对使用这些工具收集的数据的解释导致了以下假设， DFMO对卡氏肺孢子虫具有选择性毒性的一个原因是，与哺乳动物不同， 细胞，卡氏肺孢子虫不调节多胺催化剂。 另一 解释导致预测DFMO将是最有效的，当 作为连续输注给药，在动物中证实了预测 模型 关于卡氏肺孢子虫多胺代谢的进一步信息， 预计将导致新的改进，包括确定其他 多胺代谢中的代谢靶点。 以下研究将 被执行。 DFMO诱导多胺快速耗竭的机制将 通过研究多胺的排泄和表征 分解代谢和补救酶亚精胺/精胺乙酰转移酶 和多胺氧化酶（PAO）。 卡氏肺孢子虫的动态 多胺代谢的研究将侧重于相对 多胺从头生物合成与多胺降解重要性 主持人 多胺转运蛋白和生物合成酶将被 表征了 一组化合物已经被证明可以调节 其他细胞的多胺代谢将被用作卡氏肺孢子虫的探针 多胺代谢 还将研究这些化合物的 操纵多胺转运和代谢的能力， 它们在体外抑制卡氏肺孢子虫生长的能力。

DESCRIPTION: (Adapted from applicant's abstract). Pneumocystis carinii pneumonia (PCP) affects over 50% of patients with AIDS. DL-alpha-difluoromethylornithine (DFMO, eflornithine), an inhibitor of one key enzyme of polyamine biosynthesis, has been used as an alternative treatment for PCP. While DFMO is less toxic than most PCP therapies, efficacy is also lower so that it is not currently considered as a therapy for this disease. New tools have been developed in this laboratory for studies of P. carinii and for studies of polyamine metabolism. Interpretation of data collected with these tools led to the hypothesis that one reason DFMO is selectively toxic to P. carinii is that, unlike mammalian cells, P. carinii does not regulate polyamine catabolism. Another interpretation led to the prediction that DFMO would be most effective when administered as a continuos infusion, a prediction confirmed in an animal model. Further information on P. carinii polyamine metabolism can be expected to lead to new improvements including identification of other metabolic targets within polyamine metabolism. The following studies will be performed. The mechanism of DFMO-induced rapid polyamine depletion will be determined by studying excretion of polyamines and by characterizing the catabolic and salvage enzymes spermidine/spermine acetyl transferase (SSAT) and polyamine oxidase (PAO), respectively. The dynamics of P. carinii polyamine metabolism will be studied with emphasis on the relative importance of de novo polyamine biosynthesis vs scavenge of polyamines from the host. Polyamine transporter (s) and biosynthetic enzymes will be characterized. A panel of compounds which have been shown to modulate polyamine metabolism in other cells will be used as probes of P. carinii polyamine metabolism. These compounds will also be studied for their ability to manipulate polyamine transport and metabolism as well as for their ability to inhibit P. carinii growth in vitro.