Development of a Novel Therapeutic for Mitigating Radiation-Induced Microbiome Dysbiosis and Acute Gastrointestinal Syndrome

摘要 大规模伤亡的辐射事件，如简易核装置的引爆或放射性扩散 装置，可能导致严重出血、多器官衰竭和感染，可能导致败血症和/或 死亡。造血系统和胃肠道是最脆弱的组织之一。 辐射损伤。大剂量辐射导致以微生物群失调、破坏为特征的GI综合征 粘膜层、肠上皮屏障功能障碍和异常炎症反应 进一步的胃肠道损伤可能导致快速死亡的恶性循环。尽管已经在以下方面取得了进展 对抗造血急性辐射综合征的直接影响，未获FDA批准 存在可以治疗辐射引起的胃肠道损伤的对策。为了满足这一关键需求，Synedgen Inc. 开发了一种糖共聚物放射性增强剂(MIIST305)，它专门针对胃肠道，可以 潜在地改善辐射的有害影响。这种治疗药物已被证明能减少细胞 死亡，抑制局部和全身炎症，促进组织再生 炎症性肠病。我们的初步研究表明，MIIST305可以显著延长 大剂量全身x射线照射小鼠，照射后24小时给药。此外， MIIST305似乎促进了促炎消退，并维持了更正常的肠道微生物区系组成 作为对胃肠道损伤的回应。我们假设MIIST305维持粘膜层的完整性，因此 保护健康的微生物群以应对辐射，最大限度地减少对肠道上皮屏障的破坏 功效和消炎消炎。为了检验这一假设，我们提出了两个具体目标。在目标1中，我们将 进行纵向结构和功能研究，以确定急性剂量、局部身体的影响 5%骨髓照射对胃肠道结构完整性、肠道微生物区系组成的影响 和多样性，以及炎症与MIIST305缓解的动物相比。在目标2中，我们将定义 MIIST305调节的共生微生物区系组成，并阐明导致 MIIST305抑制促炎反应，最终减轻辐射诱导的毒性， 使用转基因小鼠模型和基于细胞的分析。为了解决这笔资金的首要目标 宣布，我们建议(A)探索微生物群如何影响辐射损伤的严重程度，(B)发展 辐射后24小时开始有效对抗放射性胃肠道损伤的新对策 以及(C)确定反措施的行动机制，这将提供必要的 根据《动物条例》要求FDA批准的信息。

SUMMARY A mass casualty radiation event, such as the detonation of an improvised nuclear device or radiological dispersal device, could lead to severe hemorrhage, multi-organ failure, and infection, potentially leading to sepsis and/or death. The hematopoietic system and the gastrointestinal (GI) tract are among the most vulnerable tissues to radiation injury. High-dose radiation results in GI syndrome characterized by microbiome dysbiosis, destruction of mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses that initiate a vicious cycle of further GI tract damage that can lead to rapid death. Although progress has been made to counteract the immediate effects of hematopoietic acute radiation syndrome, no FDA-approved countermeasures exist that can treat radiation-induced GI injury. To meet this critical need, Synedgen Inc., has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract that could potentially ameliorate the deleterious effects of radiation. The therapeutic drug has been shown to reduce cell death, suppress local and systemic inflammation, and improve tissue regeneration in models associated with inflammatory bowel disease. Our preliminary studies have shown that MIIST305 confers significant survival to mice exposed to high-dose partial body x-irradiation, when administered 24 hours post-irradiation. Furthermore, MIIST305 appears to promote pro-inflammatory resolution and maintain more normal gut microbiota composition in response to GI injury. We hypothesize that MIIST305 maintains the integrity of the mucosal layer thus preserving a healthy microbiome in response to irradiation, minimizing disruption of intestinal epithelial barrier function and alleviating inflammation. To test this hypothesis, we propose two specific aims. In Aim 1, we will perform longitudinal structural and functional studies to determine the impact of acute dose, partial body irradiation with 5% bone marrow sparing on GI architectural integrity, commensal gut microbiota composition and diversity, and inflammation compared to MIIST305-mitigated animals. In Aim 2, we will define the importance of MIIST305-regulated commensal microbiota composition and elucidate the molecular pathways leading to MIIST305 suppression of the pro-inflammatory response and ultimately, mitigation of radiation-induced toxicity, using both transgenic mouse models and cell-based assays. To address the overarching goals of this funding announcement, we propose to (a) explore how the microbiome affects severity of radiation injury, (b) develop novel countermeasures against radiation-induced GI damage with efficacy starting 24 hours after radiation exposure, and (c) define the mechanism of action of the countermeasures, which will provide the necessary information for FDA approval under the Animal Rule.