Radiation-Induced Paneth Cell Dysfunction

辐射引起的潘氏细胞功能障碍

基本信息

批准号：
10474225
负责人：
RADHAKRISHNA RAO
金额：
$ 49.16万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
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/10474225
关键词：
Anti-Bacterial Agents Attenuated Bacteria Biology Bone Marrow Cell physiology Clinical Colitis Data Defensins Diet Dose Down-Regulation Effectiveness Endotoxemia Enterobacteriaceae Epithelial Epithelial Cells 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 Production Protein Isoforms RNA Radiation Radiation Accidents Radiation Dose Unit Radiation Injuries Radiation Toxicity Radiation exposure Research Rodent Role Salmonella typhimurium Small Intestines Supplementation Survival Rate T cell factor 4 Testing Therapeutic Time WNT Signaling Pathway 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 response subcutaneous systemic inflammatory response transcription factor

项目摘要

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受到辐射的影响日益引起全球关注。放射综合征 (ARS) 与高发病率和死亡率相关，但 FDA 尚未批准因此，描述了放射治疗的胃肠道（GI）ARS的机制。制定有针对性的医疗对策（MCM）是胃肠道粘膜免疫的重中之重。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该领域的空白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 内毒素血症和全身炎症是与辐射相关的常见病症。 ARS 的发病率和死亡率临床和实验证据表明肠道菌群失调。（有益物种减少、致病生物增加和多样性减少）是发展为内毒素血症、全身性炎症和 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。我们的初步数据显示，人类潘氏细胞产生两种α-防御素 - 防御素 5 (HD5) 和 6 (HD6)。电离辐射会减少小鼠肠道中的 1) 消耗潘氏细胞 a-防御素，2) 粘膜 Tcf4 mRNA，3) 改变微生物群组成，4) 破坏上皮屏障，5) 随之而来的粘膜重要的是，HD5 给药于炎症反应、内毒素血症和全身炎症。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。。