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.

本项目的目标是最终开发出一种有效、实用、可广泛使用的