TREATMENT OF BPD USING MIMETICS OF SUPEROXIDE DISMUTASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 大多数患有呼吸窘迫综合征的早产儿都会接受高浓度氧气和增加呼吸道压力的治疗。在幸存者中，20%到30%的人患上了一种名为支气管肺发育不良(BPD)的慢性肺部疾病。超氧阴离子(O2-)和其他自由基引起的组织损伤与BPD的发病机制有关。我们合成了一类新颖的小分子锰(III)卟啉类超氧化物歧化酶(SOD)和过氧化氢酶。这些化合物在细胞培养和整个动物氧化应激模型中被证明是有效的阻断损伤。现在的初步结果表明，这些超氧化物歧化酶模拟物将有效地保护早产儿BPD的氧化应激成分。我们建议设计、合成和表征具有高SOD活性的锰(III)-卟啉，它可以输送到位于肺细胞内和细胞外空间的关键靶点。新的超氧化物歧化酶模拟物的有效性将通过圣安东尼奥的支气管肺资源中心在BPD上进行测试。我们在这项建议中的具体目标是：1)确定我们现有的铅SOD模拟物的药代动力学/毒性特征；2)设计和开发新的SOD模拟物；3)在非灵长类动物的氧化损伤模型中筛选新的SOD模拟物；4)在狒狒BPD中测试SOD模拟物；以及5)确定SOD模拟物在BPD模型中的作用模式。我们期望这些研究能为氧化应激在BPD中的作用提供新的见解，并提供一种新的治疗方法来减少这种破坏性疾病对早产儿的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. High concentrations of oxygen and increased airway pressure are administered to most preterm neonates with respiratory distress syndrome. Among the survivors, 20 percent to 30 percent develop a form of chronic lung disease called bronchopulmonary dyplasia (BPD). Tissue damage caused by the superoxide anion (O2-) and other free oxygen radicals has been implicated in the pathogenesis of BPD. We have synthesized a class of novel, small Mn(III) porphyrin mimetics of superoxide dismutase (SOD) and catalase. These compounds have been shown to be effective in blocking injury in cell culture and whole animal models of oxidative stress. Preliminary results now suggest that these SOD mimetics will be efficacious in protecting against the oxidative stress component of BPD in premature infants. We propose designing, synthesizing, and characterizing Mn(III)-porphyrins with high SOD activity that can be delivered to critical targets located in the intracellular and extracellular spaces of the lung. The efficacy of the new SOD mimetics will be tested on BPD through use of the Bronchopulmonary Resource Center in San Antonio. Our specific goals in this proposal are to 1) determine the pharmacokinetic/toxicity profiles of our existing lead SOD mimetics; 2) design and develop new SOD mimetics; 3) screen new SOD mimetics in nonprimate models of oxidative injury; 4) test SOD mimetics in baboon BPD; and, 5) determine the mode of action of SOD mimetics in the BPD model. We expect these studies to provide new insights on the role of oxidative stress in BPD and to provide a novel new therapeutic approach to reduce the impact of this devastating disease in premature infants.