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

开发一种缓解辐射引起的微生物群失调和急性胃肠道综合症的新疗法

• 批准号: 10567515
• 负责人: Constantinos G. Broustas
• 金额: $ 53.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567515
• 关键词: 16S ribosomal RNA sequencing; Accidents; Acute; Address; Affect; Animal Model; Animals; Antibiotics; Architecture; Bacteria; Biological Assay; Bone Marrow; C57BL/6 Mouse; Cell Count; Cell Death; Cells; Cessation of life; Colon; Development; Devices; Dose; Epithelial Cells; Epithelium; Event; Exposure to; FDA approved; Functional disorder; Funding; Gastrointestinal Injury; Gastrointestinal tract structure; Germ-Free; Gnotobiotic; Goals; HMGB1 gene; HT29 Cells; Hematopoietic; Hematopoietic System; Hemorrhage; Homeostasis; Hour; Human; Immune; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intestines; Invaded; Knockout Mice; Length; Lethal Dose 50; Ligands; Lipopolysaccharides; Macrophage; Modeling; Molecular; Molecular Target; Morphology; Mucous Membrane; Mucous body substance; Multiple Organ Failure; Mus; Nuclear; Oral Administration; Pathway interactions; Pattern; Permeability; Pharmaceutical Preparations; Production; Public Health; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Protection; Radiation Toxicity; Radiation exposure; Radiology Specialty; Resolution; Role; Sepsis; Severities; Signal Pathway; Structure; Surface; Syndrome; TLR4 gene; Testing; Therapeutic; Time; Tissues; Toll-like receptors; Toxic effect; Transgenic Mice; access restrictions; animal rule; bacterial community; cell injury; commensal microbes; cytokine; drug development; dysbiosis; efficacy evaluation; fecal microbiota; gastrointestinal; gut inflammation; gut microbiota; improved; in vivo; intestinal barrier; intestinal epithelium; intestinal injury; irradiation; mass casualty; medical countermeasure; microbiome; microbiome composition; microbiota; monocyte; mouse model; novel; novel therapeutics; pathogen; preservation; public health emergency; rRNA Genes; radiation effect; radiation mitigation; radiation mitigator; radiation response; response; systemic inflammatory response; targeted treatment; timeline; tissue regeneration; transplant model; treatment group

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.

概括 大规模伤亡辐射事件，例如简易核装置爆炸或放射性扩散 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容易受到感染的组织之一 辐射损伤。高剂量辐射导致胃肠道综合征，其特征是微生物群失调、破坏 粘膜层、肠上皮屏障功能障碍以及引发炎症反应的异常炎症反应 进一步胃肠道损伤的恶性循环可能导致快速死亡。尽管已经取得了进展 抵消造血急性辐射综合征的直接影响，未经 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. 开发了一种糖聚合物放射缓解剂（MIIST305），专门针对胃肠道，可以 可能改善辐射的有害影响。该治疗药物已被证明可以减少细胞 死亡，抑制局部和全身炎症，并改善与相关模型的组织再生 炎症性肠病。我们的初步研究表明 MIIST305 赋予显着的存活率 暴露于高剂量局部 X 射线照射的小鼠，在照射后 24 小时给药。此外， MIIST305 似乎可以促进促炎症消退并维持更正常的肠道微生物群组成 应对胃肠道损伤。我们假设 MIIST305 维持粘膜层的完整性，从而 保护健康的微生物组以应对辐射，最大限度地减少对肠上皮屏障的破坏 功能和减轻炎症。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、部分身体的影响 保留 5% 骨髓的照射对胃肠道结构完整性、共生肠道微生物群组成有影响 与 MIIST305 缓解的动物相比，多样性和炎症。在目标 2 中，我们将定义重要性 MIIST305 调节的共生微生物群组成并阐明导致的分子途径 MIIST305 抑制促炎反应并最终减轻辐射引起的毒性， 使用转基因小鼠模型和基于细胞的测定。为了实现这笔资金的总体目标 公告中，我们建议 (a) 探索微生物组如何影响辐射损伤的严重程度，(b) 开发 针对辐射引起的胃肠道损伤的新对策，在辐射后 24 小时开始发挥作用 (c) 确定对策的作用机制，这将提供必要的 FDA 根据动物规则批准的信息。