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. .

由于大规模的辐射事件，公众接触辐射是全球关注的问题。急性 辐射综合征（ARS）与高发病率和死亡率有关，但没有FDA批准 胃肠道（GI）ARS的治疗。因此，描述了辐射的机制 开发目标医疗对策（MCM）的伤害是高度重点。胃肠道粘膜免疫 系统容易受到电离辐射的影响，功能失调的粘膜免疫是主要的促成 ARS发病机理的因素。该领域的差距是辐射的精确机制 损害粘膜免疫系统和免疫功能障碍介导的肠道菌群营养不良和 多器官损伤（MOI）的定义较差。我们研究的长期目标是确定辐射 - 敏感的免疫特异性途径，测试和开发新型免疫功能障碍的MCM 辐射暴露。内毒素血症和全身性炎症是与 ARS中的发病率和死亡率。临床和实验证据表明肠道营养不良 （枯竭的有益物种，病原体增加和多样性增加）是 发展内毒素，全身感染和MOI。 A-防御素是分泌的抗菌辣椒 从高度专业的肠上皮细胞Paneth细胞中，以维持菌群稳态。 人类泛元细胞产生两个A-防御素-Defensin 5（HD5）和6（HD6）。我们的初步数据显示 小鼠肠中的电离辐射1）耗尽paneth paneth cell a-defensins，2）减少粘膜TCF4 mRNA，3）改变微生物群的组成，4）破坏上皮屏障和5）随之而来的粘膜 炎症反应，内毒素血症和全身感染。重要的是，HD5在 辐射后24小时减轻饮食会改变肠道菌群，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HD5的中心假设” GI-ARS通过逆转肠道菌群和上皮屏障功能障碍的逆转，导致缓解 内毒素血症和全身性炎症。“我们将通过确定1）电离来检验这一假设 辐射下调肠道细胞中的Wnt信号传导，2）TCF4下调培养基 辐射诱导的A-防御素的耗竭和随之而来的营养不良，3）补充A-防御素的逆转 辐射诱导的肠道菌群营养不良，4）辐射诱导的营养不良驱动肠道屏障功能障碍， 内毒素血症和全身性炎症，5）最低，最有效的HD5剂量可缓解GI- ARS，6）HD5反向GI-AR的暴露后（+24-96 h）有效性的理想时间窗口， 7）HD5治疗范例可提高致命剂量辐射的存活率。 。