New Approaches for Development of PcP Therapy

开发 PcP 治疗的新方法

• 批准号: 6747924
• 负责人: Melanie T Cushion
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747924
• 关键词: AIDS; AIDS therapy; Pneumocystis carinii; Pneumocystis pneumonia; adenosine triphosphate; ampicillin; antifungal antibiotics; combination chemotherapy; cytochrome b; drug interactions; drug screening /evaluation; fungal genetics; gene expression; laboratory rat; method development; microarray technology; mitochondria; nonhuman therapy evaluation; opportunistic infections; pentamidine; pharmacokinetics; polymerase chain reaction; respiratory disorder chemotherapy; steroid biosynthesis; sterols; sulfamethoxazole; tissue /cell culture

DESCRIPTION (provided by applicant): Pneumocystis carinii (PcP) remains an important cause of infection in immunocompromised hosts including patients with AIDS. The most widely utilized therapy is trimethoprim-sulfamethoxazole (TMP-SMX). Recent concerns have arisen over development of mutations to the DHPS locus, which mediates sensitivity to SMX. Accordingly, Dr. Cushion proposes new strategies to develop treatments for Pneumocystis based upon a better understanding of the sterol and mitochondrial metabolism pathways as potential targets for therapy. They propose to first identify efficacious compounds which target enzymatic steps in the sterol biosynthetic and mitochondrial pathways of Pc using in vitro viability assay. Under the second aim, they will assess the potential mechanisms of action of these inhibitors on each pathway by analysis of gene expression using macroarrays. In the third aim, they will attempt to identify synergistic combinations of the sterol ad mitochondrial inhibitors within and between these pathways by construction of inhibitor isobolograms. Finally, they will select the most efficacious combinations of agents and evaluate their effects on gene expression again using the macroarray approach.

描述（由申请人提供）： 卡氏肺囊虫 (PcP) 仍然是免疫功能低下宿主（包括艾滋病患者）感染的重要原因。 最广泛使用的疗法是甲氧苄啶-磺胺甲恶唑 (TMP-SMX)。 最近人们担心 DHPS 位点发生突变，该位点介导对 SMX 的敏感性。因此，Cushion 博士基于对作为潜在治疗目标的甾醇和线粒体代谢途径的更好理解，提出了开发肺孢子虫治疗方法的新策略。 他们建议首先使用体外活力测定来鉴定针对PC的甾醇生物合成和线粒体途径中的酶促步骤的有效化合物。 在第二个目标下，他们将通过使用宏阵列分析基因表达来评估这些抑制剂对每个途径的潜在作用机制。 在第三个目标中，他们将尝试通过构建抑制剂等效线图来确定这些途径内和之间的甾醇和线粒体抑制剂的协同组合。 最后，他们将选择最有效的药物组合，并使用宏阵列方法再次评估它们对基因表达的影响。