Radiation-Induced Paneth Cell Dysfunction

辐射引起的潘氏细胞功能障碍

• 批准号: 10686031
• 负责人: RADHAKRISHNA RAO
• 金额: $ 52.05万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686031
• 关键词: Anti-Bacterial Agents; Attenuated; Bacteria; Biology; Bone Marrow; Cell physiology; Cell secretion; Clinical; Colitis; Data; Defensins; Diet; Dose; Down-Regulation; Effectiveness; Endotoxemia; Enterobacteriaceae; Epithelial Cells; Epithelium; Exposure to; FDA approved; Fibroblasts; Functional disorder; Goals; Growth; Homeostasis; Human; Immune; Immune System Diseases; Impairment; Inflammatory Response; Intestinal Mucosa; Intestines; Ionizing radiation; Knockout Mice; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Mucosal Immune System; Mucosal Immunity; Mucositis; Mucous Membrane; Mus; Natural Immunity; Outcome Study; Paneth Cells; Pathogenesis; Pathway interactions; Peptides; Predisposition; Production; Protein Isoforms; Qualifying; RNA; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Toxicity; Radiation exposure; Research; Rodent; Role; Salmonella typhimurium; Small Intestines; Supplementation; Survival Rate; TCF7L2 gene; Testing; Therapeutic; Time; WNT Signaling Pathway; alpha-Defensins; antimicrobial peptide; base; cryptdin; dysbiosis; fecal transplantation; gastrointestinal; gastrointestinal epithelium; gut dysbiosis; gut microbiota; insect defensin A; intestinal crypt; intestinal epithelium; irradiation; medical countermeasure; metatranscriptome; microbiota; mortality; mouse model; multiorgan injury; novel; pathobiont; pathogen; radiation effect; radiation mitigation; response; subcutaneous; systemic inflammatory response; transcription factor

Public exposure to radiation due to large-scale radiation incidents is a rising global concern. Acute radiation syndrome (ARS) is associated with high morbidity and mortality, but no FDA-approved therapeutics for gastrointestinal (GI) ARS. Therefore, delineating the mechanisms underlying radiation injury to develop targeted medical countermeasures (MCM) is a high priority. The GI mucosal immune system is susceptible to ionizing radiation, and dysfunctional mucosal immunity is a major contributing factor in the pathogenesis of ARS. The gap in this field is that the precise mechanisms by which radiation impairs the mucosal immune system and immune dysfunction-mediated dysbiosis of gut microbiota and multi-organ injury (MOI) are poorly defined. The long-term goal of our research is to identify the radiation- sensitive immune-specific pathways and test and develop novel immune dysfunction-targeted MCM for radiation exposure. Endotoxemia and systemic inflammation are common conditions associated with morbidity and mortality in ARS. Clinical and experimental evidence indicates that intestinal dysbiosis (depleted beneficial species, increased pathobionts, and decreased diversity) is a prerequisite for developing endotoxemia, systemic inflammation, and MOI. a-Defensins are antibacterial peptides secreted from Paneth cells, the highly specialized intestinal epithelial cells, to maintain microbiota homeostasis. Human Paneth cells produce two a-defensins - defensin 5 (HD5) and 6 (HD6). Our preliminary data show that ionizing radiation in mouse intestine 1) depletes Paneth cell a-defensins, 2) reduces mucosal Tcf4 mRNA, 3) alters microbiota composition, 4) disrupts epithelial barrier, and 5) consequent mucosal inflammatory response, endotoxemia, and systemic inflammation. Importantly, HD5 administered in the diet at 24 h post-irradiation mitigates altered gut microbiota, gut barrier dysfunction, and endotoxemia. These findings form the scientific premise (FIG 1) and support the central hypothesis that “HD5 mitigates GI-ARS by reversing dysbiosis of gut microbiota and epithelial barrier dysfunction, leading to mitigation of endotoxemia and systemic inflammation.” We will test this hypothesis by determining that 1) Ionizing radiation downregulates Wnt signaling in intestinal Paneth cells, 2) TCF4 down-regulation mediates radiation-induced a-defensin depletion and consequent dysbiosis, 3) a-Defensin supplementation reverses radiation-induced dysbiosis of gut microbiota, 4) Radiation-induced dysbiosis drives gut barrier dysfunction, endotoxemia, and systemic inflammation, 5) the lowest and most effective dose of HD5 in mitigating GI- ARS, 6) the ideal time window for post-exposure (+24-96 h) effectiveness of HD5 to reverse GI-ARS, and 7) the HD5 treatment paradigm to increase the survival rates from lethal dose radiation. .

大规模辐射事件导致公众暴露于辐射是全球日益关注的问题。急性 放射综合征 (ARS) 与高发病率和死亡率相关，但 FDA 尚未批准 胃肠道 (GI) ARS 的治疗。因此，描述辐射的机制 制定有针对性的医疗对策（MCM）是重中之重。胃肠道粘膜免疫 系统易受电离辐射影响，粘膜免疫功能失调是一个主要原因 ARS 发病机制中的重要因素。该领域的差距在于辐射的精确机制 损害粘膜免疫系统和免疫功能障碍介导的肠道菌群失调， 多器官损伤（MOI）的定义不明确。我们研究的长期目标是确定辐射 敏感的免疫特异性途径，并测试和开发新型针对免疫功能障碍的 MCM 辐射暴露。内毒素血症和全身炎症是与以下疾病相关的常见病症 ARS 的发病率和死亡率。临床和实验证据表明肠道菌群失调 （有益物种枯竭、致病生物增加和多样性减少）是 出现内毒素血症、全身炎症和 MOI。 α-防御素是分泌的抗菌肽 来自潘氏细胞（高度专业化的肠上皮细胞），以维持微生物群稳态。 人类潘氏细胞产生两种α-防御素 - 防御素 5 (HD5) 和 6 (HD6)。我们的初步数据显示 小鼠肠道中的电离辐射 1) 消耗潘氏细胞 a-防御素，2) 减少粘膜 Tcf4 mRNA，3) 改变微生物群组成，4) 破坏上皮屏障，5) 随之而来的粘膜 炎症反应、内毒素血症和全身炎症。重要的是，HD5 管理于 照射后 24 小时的饮食可减轻肠道微生物群的改变、肠道屏障功能障碍和内毒素血症。 这些发现构成了科学前提（图 1）并支持“HD5 减轻 GI-ARS 通过逆转肠道菌群失调和上皮屏障功能障碍，从而缓解 内毒素血症和全身炎症。”我们将通过确定 1) 电离来检验这一假设 辐射下调肠道潘氏细胞中的 Wnt 信号传导，2) TCF4 下调介导 辐射引起的α-防御素耗竭和随之而来的生态失调，3）补充α-防御素可以逆转 辐射引起的肠道菌群失调，4）辐射引起的菌群失调会导致肠道屏障功能障碍， 内毒素血症和全身炎症，5) HD5 缓解胃肠道反应的最低和最有效剂量 ARS，6) HD5 暴露后（+24-96 小时）有效性逆转 GI-ARS 的理想时间窗口，以及 7) HD5 治疗范例，以提高致命剂量辐射的存活率。 。