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

项目总结/摘要-总体 国际辐射对抗合作联盟（Inter-collaborative Radiation Countermeasures，简称INTERACT）成立于1999年， 目标是开发安全有效的医疗对策（MCM），以减轻和/或治疗急性， 在发生核爆炸时， 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)与急性放射病（ARS）和急性辐射照射的延迟效应相关的失败 （DEARE）需要一种全面的、多学科的方法来有效地识别治疗的新靶点。 干预，并将有前途的MCM从研究实验室转移到先进的制药 根据美国食品药品监督管理局（FDA）的动物规则（AR）法规进行开发和批准 通路INTERACT是一个新成立的马里兰州医学院（UMSOM）中心， 医学辐射对策（CMCR）是国际公认的研究人员的合作伙伴关系 四个美国-在MCM开发方面拥有广泛专业知识的大学，一套独特的 动物模型平台，以及分享想法和质量实践的共同目标， 科学发现和MCMs的转化发展。 INTERACT项目广泛围绕一个共同的主题设计，通过以下方式促进组织再生： 靶向参与细胞变性的生物学过程，这些细胞变性有助于临床表现， ARS/DEARE后迅速暴露于高剂量的全身照射（TBI）。候选MCM 研究目标是与辐射诱导加速老化过程相关的关键生物学机制 包括基因组不稳定性、线粒体损伤、细胞衰老和炎症， ARS的造血（项目1）和胃肠道亚综合征（项目2，3），皮肤辐射损伤 （项目3）和DEARE（项目1和4）。调查中的每项MCM的初步数据 项目1-4已经显示出在施用后至少24小时的存活率的显著改善。 在临床前试验和某些临床试验中，推进MCM 在所有人群亚群的AR调节途径框架内开发，项目包括 由两个服务核心（核心A-管理，核心B-多物种功效和药理学）提供支持 建模核心）和两个联盟核心（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，可用于 在更广泛的CMCR联盟内进行MCM试验，包括兔、小型猪和非人灵长类动物模型 的ARS和/或DEARE。 INTERACT目前通过提供能力和资源，与其他潜在的中心协同增效。 通过数据和资源共享以及技术转让， 国家过敏和传染病研究所（NIAID）/国家卫生研究所（NIH）的使命是 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.