Mitigation of Radiation-Induced Pulmonary Injury with Nrf2 activator

Nrf2 激活剂减轻辐射引起的肺损伤

• 批准号: 8660639
• 负责人: ZELJKO VUJASKOVIC
• 金额: $ 67.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660639
• 关键词: Acute; Antioxidants; Apoptosis; Attenuated; Benchmarking; Biological Assay; Biological Markers; Blood; C57BL/6 Mouse; Cells; Chest; Development; Dose; Drug Kinetics; Event; Exposure to; FDA approved; Failure; Fibrosis; Goals; Guidelines; Hematopoietic; Hemibody Irradiation; Immune response; Inbred CBA Mice; Incidence; Individual; Inflammation; Inflammatory; Injury; Interleukin-6; Investigational New Drug Application; Knockout Mice; Laboratories; Lead; Low Dose Radiation; Lung; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Mouse Strains; Mus; Nuclear; Nuclear Accidents; Oral Administration; Organ; Oxidative Stress; Pathologic Processes; Pharmaceutical Preparations; Pharmacodynamics; Phospholipids; Plasma; Plasma Cells; Pleural effusion disorder; Pneumonia; Process; Radiation; Radiation Pneumonitis; Radiation Syndromes; Radiation Toxicity; Reactive Oxygen Species; Recovery; Regimen; Research; Research Design; Research Personnel; Respiratory distress; Risk; Rodent; Signal Transduction; Soil; Structure of parenchyma of lung; Supportive care; Syndrome; Testing; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Universities; Whole-Body Irradiation; animal rule; base; cytokine; experience; gastrointestinal; improved; irradiation; lung development; lung injury; mass casualty; mortality; nonhuman primate; novel therapeutics; prevent; product development; public health relevance; response; success; treatment duration

DESCRIPTION (provided by applicant): Anecdotal experience with nuclear accident victims has shown that with superior supportive care, individuals may survive the acute radiation syndromes (hematopoietic and gastrointestinal syndromes), but ultimately succumb to respiratory distress due to radiation pneumonitis/fibrosis as a delayed effect. At this time there s no FDA approved treatment for radiation pneumonitis/fibrosis. Therefore, the goal of this project is to finalize the development of a safe, effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced pulmonary injury by utilizing a Nrf2 activator, trifluoromethyl-2'-methoxychalone (TMC) developed at Johns Hopkins University (JHU). The rationale for Nrf2 activator as a medical countermeasure arises from a decade of research demonstrating that augmenting Nrf2 signaling will inhibit oxidative stress, apoptosis, aberrant immune response, and inflammation (the 4 key pathologic processes involved in radiation-induced pulmonary injury) by upregulating a broad spectrum of cytoprotective defenses including nearly all cellular antioxidants. The studies proposed here will be focused on further development of TCM. The objective of this proposal is to bring TMC towards pivotal efficacy studies under GLP guidelines in rodent and non-human primates for Investigational New Drug (IND) application and FDA approval under the Animal Rule. The proposal comprises seven specific Milestones and defines benchmarks for determining their success. Specifically, the studies are designed to determine the maximum tolerated dose (MTD), tissue and plasma PK, establish a pharmacodynamics assay based on the mechanism of the compound, and to define the optimal dose, treatment duration, and window of opportunity for initiation of TMC treatment to optimize therapeutic efficacy and maximally improve survival.

描述（由申请人提供）：核事故受害者的轶事经验表明，在良好的支持性护理中，个体可以在急性辐射综合症（造血和胃肠道综合症）中生存，但最终由于延迟效应而屈服于辐射性肺炎/纤维化引起的呼吸窘迫。此时，尚无FDA批准用于放射肺炎/纤维化的治疗方法。因此，该项目的目的是通过利用在约翰斯·霍普金斯大学（JHU）开发的NRF2激活剂，三氟甲基-2'-甲氧甲酮（TMC），通过利用NRF2激活剂，三氟2'-甲氧甲酮（TMC）来最终确定安全，有效，可用的医学对策，以减轻和/或治疗辐射引起的肺部损伤。 The rationale for Nrf2 activator as a medical countermeasure arises from a decade of research demonstrating that augmenting Nrf2 signaling will inhibit oxidative stress, apoptosis, aberrant immune response, and inflammation (the 4 key pathologic processes involved in radiation-induced pulmonary injury) by upregulating a broad spectrum of cytoprotective defenses including nearly all cellular antioxidants.这里提出的研究将集中在TCM的进一步发展上。该提案的目的是根据GLP指南将TMC带入啮齿动物和非人类灵长类动物的GLP指南，以进行研究新药（IND）应用，并根据动物规则获得FDA批准。该提案包括七个特定的里程碑，并定义了确定其成功的基准。具体而言，研究旨在确定最大耐受剂量（MTD），组织和血浆PK，基于该化合物的机制建立药效学测定法，并定义最佳剂量，治疗持续时间和机会范围，以启动TMC治疗以使治疗效率和最大程度地提高生存率。