Manganese SOD transgene product and SOD small molecules

在啮齿动物模型中，在电离辐射暴露之前（或之后）通过转基因治疗过度表达锰超氧化物歧化酶（MnSOD），可显著降低急性和慢性辐射引起的损伤，并减少肺、食管、口腔、肠道和膀胱组织产生的自由基氧。我们的实验室已经证明，在器官特异性基因治疗后48至72小时内可以检测到MnSOD转基因mRNA和表位标记的ha -血凝素MnSOD蛋白过表达，并且连续给药多剂量的MnSOD质粒脂质体（PL）可通过口服或吸入途径实现稳定的放射性保护转基因表达。我们还表明，小分子SOD模拟化合物减少急性和慢性辐射损伤。我们现在将优化SOD抗氧化治疗的辐射防护和减轻辐射损伤。第一个具体目的是测试MnSOD-PL将是一种有效的全身照射（WB1）系统保护剂的假设。我们将测量MnSOD-PL处理和转基因mnsod小鼠组织中自由基氧（ROS）的产生、硫醇和抗氧化剂池的变化；在一种新型的可诱导的MnSOD转基因小鼠模型中，将测定MnSOD过表达相对于WBI前后时间的放射防护水平、毒性、致癌性和晚期效应。第二个特定目的是验证新设计和合成的以抗氧化剂EUK-134为基准的小分子SOD模拟化合物将有效替代MnSOD-PL基因治疗或与之协同作用的假设。创新药物化学：发现和筛选核心将与我们合作开发一种全身口服或皮肤贴片可吸收的药物产品。第三个具体目的是验证在优化的线粒体靶向SOD模拟物和MnSOD-PL方案中添加氮氧化物、过氧化氢酶或谷胱甘肽过氧化物酶（GPX）将进一步提高辐射防护和辐射缓解的假设。这些研究应该优化利用抗氧化转基因和小分子SOD模拟治疗来保护电离辐射损伤。

Overexpression of manganese superoxide dismutase (MnSOD) by transgene therapy prior to (or after) ionizing irradiation exposure significantly decreases both acute and chronic irradiation-induced damage and reduces radical oxygen species production by pulmonary, esophageal, oral cavity, intestinal, and bladder tissues in rodent models. Our laboratory has demonstrated that MnSOD transgene mRNA, and epitope-tagged HA-hemagglutinin MnSOD protein overexpression are detectable for 48 to 72 hours after organ specific gene therapy and that sequential administration of multiple doses of MnSOD-Plasmid Liposomes (PL) results in stable radioprotective transgene expression by the intra-oral or inhalation route. We have also shown that small molecule SOD mimetic compounds decrease acute and chronic irradiation damage. We will now optimize SOD antioxidant therapy for radiation protection and radiation injury mitigation. The first specific aim tests the hypothesis that MnSOD-PL will be an effective systemic protector against whole body irradiation (WB1). We will measure radical oxygen species (ROS) production, changes in thiols and antioxidant pools in tissues from MnSOD-PL treated, and MnSOD-transgenic mice; and in a novel tet-inducible MnSOD transgenic mouse model, will determine the level of radioprotection, toxicity, carcinogenicity and late effects of MnSOD overexpression relative to time before or after WBI. The second specific aim tests the hypothesis that newly designed and synthesized small molecule SOD mimetic compounds which are mitochondrially targeted by peptide dragging, and benchmarked to the antioxidant, EUK-134, will effectively substitute for or synergize with MnSOD-PL gene therapy. The Innovative Medicinal Chemistry: Discovery and Screening Core will collaborate with us to develop a systemic oral or skin patch absorbable drug product. The third specific aim tests the hypothesis that adding nitroxide, catalase or glutathione peroxidase (GPX) to the optimized protocol of mitochondrial targeted SOD mimetic and MnSOD-PL will further improve both radioprotection and radiation mitigation. These studies should optimize utilization of both antioxidant transgene and small molecule SOD mimetic therapy for protection from ionizing irradiation damage.