Radiation Protection with SOD Mimetics

SOD 模拟物的辐射防护

• 批准号: 8306950
• 负责人: ZELJKO VUJASKOVIC
• 金额: $ 26.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306950
• 关键词: Acute; Animals; Antioxidants; Apoptosis; Apoptotic; Biological Availability; Chest; Collaborations; Development; Dose; Drug Formulations; Drug Kinetics; Emergency Situation; Event; Exposure to; Fibrosis; Funding; Gene Expression; Genes; Goals; Hematopoietic; Hour; Incidence; Inflammation; Injury; Intestines; Low Dose Radiation; Lung; Maximum Tolerated Dose; Mediating; Medical; Medical center; Metalloporphyrins; Modeling; Molecular; Mouse Strains; Mus; NADPH Oxidase; Oral; Oral Administration; Oxidation-Reduction; PTEN gene; Pathway interactions; Plasma; Play; Porphyrins; Primates; Radiation; Radiation Pneumonitis; Radiation Protection; Radiation Sicknesses; Radiation Toxicity; Regimen; Respiratory physiology; Rodent; Rodent Model; Role; Saline; Signal Transduction; Subcutaneous Injections; Superoxide Dismutase; Syndrome; Techniques; Testing; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Tissues; Whole-Body Irradiation; base; design; drinking water; experience; gastrointestinal; improved; irradiation; lung injury; mimetics; mouse model; nonhuman primate; novel; research study; response; subcutaneous; weapons of mass destruction

The goal of this project is to finalize the development of an effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced lung injury using a metalloporphyrin antioxidant compound, MnTnHex-2-PyP5+ developed during the last funding period. The rationale for metalloporphyrin mimetics as medical countermeasures arises from well-characterized pathophysiological pathways, which rely on redox signaling, that underiy the development of radiation-induced lung injury. In the previous funding period the ability of MnTnHex-2-PyP5+ to effectively mitigate radiation-induced lung injury was demonstrated in both rodent and in non-human primate models when given at relatively low doses (0.05 mg/kg). Based on these studies, we now propose in collaboration with the Primate Core, to perform dose escalation studies to determine the optimum subcutaneous dose of MnTnHex-2-PyP5+ to improve lung function and survival after whole thorax irradiation in a NHP model (Specific Aim 1). At the same time we recognize the need for improved delivery techniques. Therefore, Specific Aim 2 is focused on development of an oral formulation of MnTnHex-2-PyP5+ which will be first tested in our rodent model (optimum dose, duration, and window of opportunity for treatment initiation) prior to efficacy studies in our NHP model, which will occur in the last year of the new funding period. Lastly, parallel studies will be conducted to determine the mechanism of action of MnTnHex-2-PyP5+ . If successful, this project will provide a safe and effective deliverable that can be stockpiled and made widely available for use in mass casualty settings after an accidental or deliberate radiation emergency.

该项目的目的是最终确定有效，实用且广泛可用的开发 使用金属甲磷脂抗氧化剂化合物减轻和/或治疗辐射诱导的肺损伤的医学对策，在最后一个融资期间开发的MNTNHEX-2-PYP5+。金属卟啉模拟物作为医学对策的基本原理是由依赖氧化还原信号传导的特征良好的病理生理途径引起的，这使辐射诱导的肺损伤的发展不足。在上一个融资期间，MNTNHEX-2-PYP5+有效减轻辐射诱导的肺损伤的能力在相对较低的剂量（0.05 mg/kg）时都证明了在啮齿动物和非人类灵长类动物模型中的能力。基于这些研究，我们现在建议与灵长类动物核心合作进行剂量升级研究，以确定MNTNHEX-2-PYP5+的最佳皮下剂量，以改善NHP模型中整个胸腔照射后的肺功能和生存（特定的AIM 1）。同时，我们认识到需要改进的交付技术。因此，具体目标2的重点是开发MNTNHEX-2-PYP5+的口服表述，该制定将在我们的NHP模型中进行疗效研究之前首先在我们的啮齿动物模型（最佳剂量，持续时间和治疗启动的机会窗口）中进行测试，而NHP模型将在新资助期的去年发生。最后，将进行平行研究以确定MNTNHEX-2-PYP5+的作用机理。如果成功的话，该项目将提供安全有效的可交付能力，可以在意外或故意辐射紧急情况下被储存并广泛用于大规模伤亡环境。