Application of CDX-MDM in Pre-Clinical Model of Murine Pulmonary Emphysema

描述(申请人提供)：这项建议的目的是开发一种新发现的抗炎功能，涉及白三烯A4水解酶的氨基肽酶活性，用于治疗肺气肿。白三烯A4水解酶是一种双功能酶，具有两种截然相反的功能。作为一种环氧化物水解酶，它在促炎过程中催化白三烯A4转化为白三烯B4。作为一种氨基肽酶，它在抗炎过程中催化Pro-Gly-Pro等三肽序列的消化。第一次，我们创造了一种药理学试剂(4-MDM)，用它可以选择性地上调白三烯A4水解酶的氨基肽酶活性。我们假设4-MDM治疗将保护肺部免受肺气肿的侵袭。初步结果表明，4-MDM治疗能有效地保护小鼠肺免受鼻腔注射弹性蛋白酶所致的肺气肿的影响。随后，我们研制了4-MDM作为潜在的口服制剂(CDX-MDM)，使其具有稳定的水溶性。CDX-MDM的水溶性增强使我们能够在慢性肺气肿动物模型中使用这种药物。在这项前期工作的基础上，我们建议在香烟烟雾诱导的小鼠肺气肿模型上进行CDX-MDM的疗效研究，香烟烟雾与人类疾病最相似。肺气肿发生在长时间的触发(香烟烟雾)暴露中。因此，开发一种衡量药物药效的生物标记物分析也可能是克服药物开发过程中起效时间较长的理想工具。我们建立了一种生物标志物，可以在体外测定血浆中白三烯A4水解酶的氨基肽酶活性。在这项赠款申请中，我们还建议用CDX-MDM或安慰剂治疗的动物的血浆样本来测试这一检测方法。总而言之，该项目将提供必要的证据，CDX-MDM将被开发为一种潜在的肺气肿治疗方法。

DESCRIPTION (provided by applicant): The objective of this proposal is to exploit a newly discovered anti-inflammatory function involving the aminopeptidase activity of the leukotriene A4 hydrolase for the treatment of pulmonary emphysema. The leukotriene A4 hydrolase is a dual-functioning enzyme with dichotomously opposing functions. As an epoxide hydrolase, it catalyzes the conversion of leukotriene A4 to leukotriene B4 in pro-inflammatory processes. As an aminopeptidase, it catalyzes the digestion of the tripeptide sequences like Pro-Gly-Pro in anti-inflammatory processes. For the first time, we have created a pharmacological agent (4-MDM) with which the aminopeptidase activity of the leukotriene A4 hydrolase can be selectively up-regulated. We hypothesized that the treatment with 4-MDM will protect lungs from developing pulmonary emphysema. Preliminary results demonstrated that the 4-MDM treatment effectively protected murine lungs from emphysema induced by intra- nasal elastase. Subsequently, we formulated 4-MDM to be stably water soluble as a potential oral agent (CDX- MDM). Enhanced water solubility of the CDX-MDM has enabled us to administer this agent in a chronic animal model of pulmonary emphysema. Building upon this preliminary work, we propose to conduct the efficacy study of the CDX-MDM in a murine model of pulmonary emphysema induced by cigarettes smoke which resembles human disease most closely. Emphysema develops over a long duration of trigger (cigarette smoke) exposure. Therefore, developing a biomarker assay which measures the pharmaceutical effects of the drug could also be a desirable tool to overcome the long duration of onset during the development of a pharmaceutical agent. We developed a biomarker assay which the aminopeptidase activity of the leukotriene A4 hydrolase can be measured in plasma ex vivo. In this grant application, we also propose to test this assay with the plasma samples from the animals treated with the CDX-MDM or placebo. In combination, this project will provide necessary evidence on which the CDX-MDM will be developed as a potential therapy for emphysema.