TREATMENT OF BPD USING MIMETICS OF SUPEROXIDE DISMUTASE

使用超氧化物歧化酶模拟物治疗 BPD

• 批准号: 7716049
• 负责人: James D Crapo
• 金额: $ 2.26万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716049
• 关键词: Animal Model; Chronic lung disease; Class; Computer Retrieval of Information on Scientific Projects Database; Cultured Cells; Disease; Drug Kinetics; Extracellular Space; Funding; Goals; Grant; Injury; Institution; Lead; Lung; Modeling; Newborn Respiratory Distress Syndrome; Oxidative Stress; Oxygen; Papio; Pathogenesis; Porphyrins; Premature Infant; Research; Research Personnel; Resources; Role; Source; Superoxide Dismutase; Superoxides; Survivors; Testing; Tissues; Toxic effect; United States National Institutes of Health; catalase; design; free radical oxygen; insight; mimetics; novel; novel therapeutics; pressure

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 高浓度氧气和气道压力增加管理的大多数早产儿呼吸窘迫综合征。 在幸存者中，20%到30%的人患上了一种叫做支气管肺发育不良（BPD）的慢性肺病。 超氧阴离子（O2-）和其他氧自由基引起的组织损伤与BPD的发病机制有关。 我们已经合成了一类新的，小锰（III）卟啉模拟超氧化物歧化酶（SOD）和过氧化氢酶。 这些化合物已被证明在细胞培养和氧化应激的整个动物模型中有效阻断损伤。 初步结果表明，这些SOD模拟物将有效地保护早产儿免受BPD的氧化应激成分。 我们建议设计，合成和表征Mn（III）-卟啉具有高SOD活性，可以提供给位于细胞内和细胞外空间的肺的关键目标。 新的SOD模拟物的功效将通过使用圣安东尼奥的支气管肺结核资源中心在BPD上进行测试。 我们在该提案中的具体目标是：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）在氧化损伤的非灵长类动物模型中筛选新的SOD模拟物; 4）在狒狒BPD中测试SOD模拟物; 5）确定SOD模拟物在BPD模型中的作用方式。 我们希望这些研究能够为氧化应激在BPD中的作用提供新的见解，并提供一种新的治疗方法，以减少这种毁灭性疾病对早产儿的影响。