Center for High-Throughput Minimally-Invasive Radiation Biodosimetry

高通量微创放射生物剂量测定中心

• 批准号: 10590249
• 负责人: DAVID JONATHAN BRENNER
• 金额: $ 17.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-26 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590249
• 关键词: Acute; Adult; Affect; Animals; Area; Bacteria; Complex; Disease; Dose; Event; Functional disorder; Funding; Gastrointestinal tract structure; Homeostasis; Indoles; Inflammatory Bowel Diseases; Injury; Intestines; Investigation; Kynurenic Acid; Link; Longevity; Mediating; Medical; Modeling; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Radiology; Outcome; Pathway interactions; Play; Propionates; Radiation; Radiation Injuries; Radiation Protection; Radiation exposure; Radiation induced damage; Radiation therapy; Radio; Role; Science; Survivors; Symptoms; Syndrome; Therapeutic; Tissues; Tryptophan; Vascular remodeling; Volatile Fatty Acids; Whole-Body Irradiation; Work; biodosimetry; cancer therapy; cell type; epithelial repair; gastrointestinal epithelium; gut microbiota; hematopoietic stem cell self-renewal; insight; intestinal epithelium; microbial community; microbiota; microbiota metabolites; microorganism; minimally invasive; radiation-induced injury; receptor

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.

摘要（30行限制）： 多器官辐射引起的伤害代表了在 意外暴露，无线电疗法或有针对性的恐怖袭击。已经做出了大量的联邦努力 减轻急性辐射症状；但是，这仍然是一个长期尚未解决的问题。肠 上皮是最快的成年组织，使其对辐射高度敏感，从而使主要敏感 环境过度暴露和放射治疗期间急性损伤的靶标。胃肠道（GI） 拥有一个复杂的微生物群落，其中包括10-100万亿微生物。微生物群具有 在多种疾病中已知的作用，例如炎症性肠病（IBD），2型糖尿病，肠道血管 重塑和神经元体内平衡。最近，有越来越多的证据与肠道菌群联系起来 辐射诱导的综合征。 我们已经表明，胃肠道菌群组成可以影响高剂量总体辐照的结果 （TBI）（科学2020）。我们描述了一个意外的发现，一小部分动物可以生存致命 TBI并过着正常的寿命。这些精英活体带有一个独特的肠道微生物群，具有保护性 反对辐射。详细的描述已缩小对TBI有益的细菌。 lachnospileaceae在增强造血干细胞再生和胃肠道中起着至关重要的作用 辐射后上皮维修。我们进一步识别出丙酸，短链脂肪酸（SCFA）和钥匙 从Lachnospileceae下游起作用的代谢产物作为有效的无线电保护剂。更引人注目的是 色氨酸途径代谢物（1H-吲哚-3-羧甲醛和kynurenic Acid）也有选择性地找到 在精英活体中，提供辐射保护。尽管我们发现了肠道之间的相关性 微生物群/代谢产物和辐射诱导的损伤，并使用这些代谢物来减轻辐射 损坏，该机制的详细基础仍在研究中。 该建议旨在阐明微生物衍生物如何改善的机制 辐射损伤。我们将专注于确定哪些细胞类型和代谢物受体起着至关重要的作用 在介导SCFA或色氨酸代谢物的辐射保护时，并确认此功能是否为 在辐射模型中由肠道菌群控制。这项工作将提供对这两种疾病的见解 病理生理学和潜在疗法，导致针对辐射的更好，更有效的治疗方法 放射线/核恐怖事件，意外暴露和 无线电疗法。