Intercollaborative Radiation Countermeasure (INTERACT) Consortium for Advanced Development of Medical Countermeasures to Mitigate/Treat Acute and Delayed Radiation Syndromes

项目摘要/摘要--总体 协同辐射对抗(InterAct)联盟为总体 开发安全有效的医学对策(MCM)以缓解和/或治疗急性、 事件中辐射暴露对所有平民群体的延迟和长期后果 放射性或核(RadNuc)公共卫生紧急情况。多器官损伤的生物学复杂性 (MOI)和与急性放射病(ARS)相关的故障以及急性辐射暴露的延迟效应 (DEARE)需要综合的、多学科的方法来有效地确定新的治疗靶点 干预和将有前途的中成药从研究实验室转移到先进制药 根据美国食品和药物管理局(FDA)动物规则(AR)监管进行的开发和批准 路径。InterAct，一个新成立的马里兰大学医学院(UMSOM)的中心 辐射医学对策(CMCR)是由国际公认的研究人员组成的合作伙伴 来自四所美国大学，他们在MCM开发方面拥有广泛的专业知识，一套独特的 动物模型平台，以及分享想法和质量实践以推动尖端技术的共同目标 中成药的科学发现和转化发展。 InterAct项目广泛围绕一个共同的主题进行设计，以通过 靶向参与细胞退变的生物学过程，这些过程有助于临床表现 ARS/DeA是在立即暴露于大剂量全身照射(TBI)后出现的。以下是候选MCMS 研究与辐射诱导的加速衰老过程相关的关键生物学机制 包括基因组不稳定、线粒体损伤、细胞衰老和导致 造血(方案1)和ARS的胃肠亚综合征(方案2、3)，皮肤辐射损伤 (项目3)和Deare(项目1和4)。年调查中的每一种中成药的初步数据 项目1-4显示，在至少24小时后给药，存活率显著提高。 在临床前试验和某些情况下的临床试验中暴露和强大的安全性。推进MCM 在所有人口亚类的AR管制路径框架内发展，项目是 由两个服务核心(核心A-管理、核心B-多物种功效和药物计量)提供支持 建模核心)和两个联合体核心(协调中心核心和机会基金 管理核心)。核心B提供了一个，如果不是最全面的动物模型平台， 在更广泛的CMCR联盟内进行MCM测试，包括兔子、小型猪和非人灵长类动物模型 ARS和/或Deare。 InterAct通过目前提供的功能和资源与其他潜在中心实现协同 其他站点无法通过数据和资源共享以及技术转让来推进和加强 国家过敏症和传染病研究所/国家卫生研究所S代表团 确保国家做好应对放射性或核事故的准备。

PROJECT SUMMARY/ABSTRACT - OVERALL The Inter-collaborative Radiation Countermeasures (INTERACT) Consortium was assembled for the overall goal of developing safe and effective medical countermeasures (MCM) to mitigate and/or treat the acute, delayed, and long-term consequences of radiation exposure for all subsets of the civilian population in the event of a radiological or nuclear (RadNuc) public health emergency. The biological complexity of multiorgan injury (MOI) and failure associated with acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE) requires a comprehensive, multidisciplinary approach to efficiently identify new targets for therapeutic intervention and to move promising MCMs from the research laboratory to advanced pharmaceutical development and approval under the U.S. Food and Drug Administration’s (FDA) Animal Rule (AR) regulatory pathway. INTERACT, a newly formed University of Maryland School of Medicine (UMSOM)-based Center for Medical Countermeasures against Radiation (CMCR), is a partnership of internationally-recognized investigators from four U.S.-based universities who possess a broad depth of expertise in MCM development, a unique set of animal model platforms, and a common goal of sharing ideas and quality practices to advance the cutting-edge scientific discovery and translational development of MCMs. INTERACT projects are broadly designed around a common theme to promote tissue regeneration through targeting the biological processes involved in cellular degeneration that contribute to the clinical manifestation of ARS/DEARE after prompt exposure to high-doses of total body irradiation (TBI). Candidate MCMs under investigation target key biological mechanisms associated with a radiation-induced accelerated aging process including genomic instability, mitochondrial damage, cellular senescence, and inflammation that leads to the hematopoietic (Project 1) and gastrointestinal subsyndromes of ARS (Projects 2, 3), cutaneous radiation injury (Project 3), and DEARE (Projects 1 and 4). Preliminary datum for each of the MCMs under investigation in Projects 1-4 have shown a significant improvement in survival when administered at least 24 hours post- exposure and strong safety profiles in preclinical, and in some cases clinical trials. To advance MCM development within the framework of the AR regulatory pathway for all subsets of the population, projects are supported by two service cores (Core A- Administrative, Core B- Multispecies Efficacy and Pharmacometric Modeling Core) and two consortium cores (Coordinating Center Core, and the Opportunities Fund Management Core). Core B offers one of, if not the most, comprehensive animal model platforms available for MCM testing within the broader CMCR consortia, and includes rabbit, minipig, and non-human primate models of ARS and/or DEARE. INTERACT is synergistic with other potential Centers by offering capabilities and resources currently unavailable to other sites through data and resource sharing and technology transfer to advance and strengthen the National Institute of Allergy and Infectious Diseases (NIAID)/National Institute of Health (NIH)’s mission to ensure the nation’s preparedness to respond to a radiological or nuclear incident.