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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. .

由于大规模辐射事件造成的公众辐射暴露是一个日益引起全球关注的问题。急性