Project 3 Innate immune receptor ligand and the microbiota as countermeasures for radiation

项目 3 先天免疫受体配体和微生物群作为辐射对策

基本信息

批准号：
10693906
负责人：
Jenny P Ting
金额：
$ 40.41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693906
关键词：
16S ribosomal RNA sequencing Acute Age Animal Model Animals Bacteria Bacteroides Binding Biodistribution Blood Blood Platelets Cardiotoxicity Cell Line Cells Cessation of life Cutaneous Data Development Disease Dose Drug Kinetics Environment Epithelial Cells Extravasation Family Fibrosis Functional disorder Funding Gastrointestinal tract structure Germ-Free Goals Grant Hematopoietic Hematopoietic System House mice Immune Immunity Immunologic Receptors Infection Inflammatory Injury Innate Immune System Ionizing radiation Ligands Link Longevity Lung Macaca mulatta Medical center Membrane Metabolic Pathway Microbe Monitor Mus Myeloid Cells Natural Immunity Organ Outcome Pathway interactions Patients Pattern recognition receptor Phase Physiological Play Prevention Probiotics Process Proteomics Radiation Radiation Injuries Radiation Protection Radiation Toxicity Radiation induced damage Recovery Role Sepsis Source Survivors Syndrome TLR2 gene Testing Tissues Toll-like receptors Toxic effect Universities Whole-Body Irradiation Wild Type Mouse Work adaptive immunity cerebrovascular commensal bacteria commensal microbes experimental study extracellular fecal transplantation feeding forest gastrointestinal germ free condition improved irradiation medical countermeasure metabolome metabolomics microbial microbiota mortality nonhuman primate novel therapeutics pathogen pathogenic microbe phosphoproteomics prevent radiation countermeasure radiation mitigation radiation mitigator radiation-induced injury receptor

项目摘要

UNC-CH SUBCONTRACT Abstract This application focuses on a central goal of the RFA for Centers for Medical Countermeasures Against Radiation to “further develop existing as well as novel therapies to minimize tissue damage, hasten tissue recovery, restore normal physiological function, and improve survival.” Multi-organ radiation-induced injury is a major threat during targeted terror attack, and adaptive and innate immunity are increasingly found to play a key role in this process. Innate immune receptors collectively referred to as Pathogen Recognition Receptors (PRR) have undergone an explosive discovery phase. Prominent PRR families include the membrane bound Toll-like receptors (TLR) which interact with extracellular ligands. These have been extensively studied in infection and inflammatory diseases, and their impact on radiation-induced damage has emerged in the last few years. Post-exposure, radiation not only causes acute injury but also delayed injury such as fibrosis and defective cellular and immune development. We and others have explored the roles of TLRs in radiation and unexpectedly found that certain TLRs and their ligands are protective of radiation-induced damage involving both the hematopoietic system as well as the gastrointestinal tissues. In addition to TLR ligands, we have also isolated beneficial microbiota and metabolites from animals that survived lethal radiation, and propose to explore if these microbes and their metabolites can mitigate radiation damage. This proposal will focus on the use and mechanism of TLR ligands, commensal microbes and their metabolites as radiation mitigators that can reduce radiation induced damage.

UNC-CH分包合同抽象的该申请的重点是用于医疗对策中心的RFA的中心目标反对“进一步开发现有和新型疗法以最小化组织的辐射损害，急速组织恢复，恢复正常的身体机能并提高生存率。” 多器官辐射引起的伤害是针对性恐怖袭击和适应性的主要威胁越来越多地发现先天免疫在此过程中起着关键作用。先天免疫统称为病原体识别受体（PRR）的受体经历了爆炸性发现阶段。著名的PRR系列包括类似膜的收费与细胞外配体相互作用的受体（TLR）。这些已被广泛研究在感染和炎症性疾病中，它们对辐射诱导的损害的影响具有在过去的几年中出现。暴露后，辐射不仅会造成急性损伤，还会导致延迟损伤，例如纤维化以及缺陷的细胞和免疫发育。我们和其他人已经探索了TLR在辐射中的作用，并意外地发现某些TLR及其配体受到保护，免受辐射诱导的损害，涉及造血系统以及胃肠道组织。除TLR配体外，我们还孤立了有益来自致命辐射的动物的微生物群和代谢产物，并提议探索是否存在这些微生物及其代谢物可以减轻辐射损害。该提议将重点放在 TLR配体，共生微生物及其代谢物作为辐射的使用和机制可以减少辐射引起的损伤的缓解剂。