Center for High-Throughput Minimally-Invasive Radiation Biodosimetry

摘要（30行限制）： 多器官辐射损伤是一个重大的未满足的医疗需求， 意外暴露、放射性癌症治疗或有针对性的恐怖袭击。联邦政府已经做出了巨大的努力 然而，这仍然是一个长期未解决的问题。肠 上皮细胞是更新最快的成人组织，使其对辐射高度敏感，因此是主要的 在环境过度照射和放射治疗期间急性损伤靶点。胃肠道（GI） 拥有复杂的微生物群落，包括10 - 100万亿个微生物。微生物群 已知在多种疾病中的作用，如炎症性肠病（IBD）、2型糖尿病、肠血管疾病、 重塑和神经元稳态。最近，越来越多的证据表明肠道微生物群 辐射引起的综合症 我们已经表明，胃肠道微生物群组成可以影响高剂量全身照射的结果 (TBI)（Science 2020）。我们描述了一个意想不到的发现，一小部分动物可以在致命的 创伤性脑损伤和正常的生活。这些精英幸存者拥有独特的肠道微生物群， 对抗辐射详细的描述缩小了有益于TBI的细菌。 毛螺菌科在增强造血干细胞再生和胃肠道中起着至关重要的作用。 辐射后的上皮修复我们进一步确定了丙酸，一种短链脂肪酸（SCFA）， 作为一种有效的辐射防护剂，其作用于毛螺菌科的下游代谢物。更引人注目的是， 色氨酸途径代谢物（1H-吲哚-3-甲醛和犬尿烯酸）也被选择性地发现 并提供辐射防护。尽管我们已经发现了肠道和 微生物群/代谢物与辐射引起的损害，以及利用这些代谢物减轻辐射 虽然这一机制的具体基础仍在调查中。 该提案旨在阐明微生物群衍生的代谢物如何改善 辐射损伤我们将集中在确定哪些细胞类型和代谢物受体发挥重要作用 通过SCFA或色氨酸代谢物介导辐射保护，并确认这种功能是否 由辐射模型中的肠道微生物群控制。这项工作将提供深入了解这两种疾病 病理生理学和潜在的治疗学，从而导致更好和更有效的抗辐射治疗 在发生放射性/核恐怖事件后受到辐射照射的情况下，意外照射，以及 放射治疗癌症

ABSTRACT (30 line limit): Multi-organ radiation-induced injury represents a significant unmet medical need that occurs during accidental exposure, radio-cancer therapy or a targeted terror attack. Substantial federal efforts have been made to mitigate acute radiation symptoms; however, it remains a long-standing and unresolved problem. Intestinal epithelium is the fastest-renewing adult tissue, making it highly sensitive to radiation and thereby the major target of acute injury during environmental overexposure and radiation therapy. The gastrointestinal (GI) tract harbors a complex microbial community that comprises 10-100 trillion microorganisms. The microbiota has known roles in multiple diseases, such as inflammatory bowel disease (IBD), type 2 diabetes, intestinal vascular remodeling and neuronal homeostasis. Recently, there is increasing evidence linking the intestinal microbiota to radiation induced syndromes. We have shown that GI microbiota composition can affect the outcome of high dose total body irradiation (TBI) (Science 2020). We described an unexpected finding that a small percentage of animals can survive lethal TBI and live a normal life span. These elite-survivors harbor a distinct gut microbiota which are protective against radiation. A detailed delineation has narrowed down the bacteria that are beneficial for TBI. Lachnospiraceae plays a vital role in enhancing hematopoietic stem cell regeneration and gastrointestinal epithelial repair post radiation. We further identified propionate, a short chain fatty acid (SCFA) and the key metabolite that acts downstream from Lachnospiraceae, to serve as a potent radio-protectant. More strikingly, tryptophan pathway metabolites (1H-indole-3-carboxaldehyde and kynurenic acid) are also selectively found in the elite-survivors and provide radioprotection. Although we have uncovered the correlation between gut microbiota/metabolites and radiation-induced damage, and the use of these metabolites to mitigate radiation damage, the detailed underpinnings of the mechanism remain under investigation. This proposal aims at elucidating the mechanism of how the microbiota derived metabolites ameliorate radiation injury. We will focus on identifying which cell types and metabolites receptors play the essential role in mediating the radioprotection by SCFA or tryptophan metabolites and confirming whether this function is controlled by the gut microbiota in the radiation model. This work would provide insight into both disease pathophysiology and potential therapeutics, leading to better and more efficient treatments against radiation injury in the cases of radiation exposure after a radiological/nuclear terrorist event, accidental exposure, and radio-cancer therapy.