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

UNC-CH分包合同 摘要 此应用程序侧重于RFA的医疗对策中心的中心目标 反对辐射“进一步发展现有的以及新的疗法，以尽量减少组织 损伤，加速组织恢复，恢复正常的生理功能，提高生存率。 多器官辐射损伤是恐怖袭击的主要威胁， 越来越多的人发现先天免疫在这一过程中起着关键作用。先天免疫 统称为病原体识别受体（PRR）的受体已经经历了一个 爆炸性发现阶段突出的PRR家族包括膜结合的Toll样 受体（TLR）与细胞外配体相互作用。这些已经被广泛研究 在感染和炎性疾病中的作用，以及它们对辐射引起的损害的影响， 在过去的几年里出现了。暴露后，辐射不仅造成急性损伤， 延迟损伤，如纤维化和有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 配体对辐射诱导的损伤具有保护作用， 以及胃肠道组织。除了TLR配体，我们还分离了有益的 微生物群和代谢物从动物中幸存下来的致命辐射，并建议探讨， 这些微生物及其代谢产物可以减轻辐射损伤。该提案将重点关注 TLR配体、肠道微生物及其代谢产物作为辐射源的应用和机制 可以减少辐射引起的损伤的缓解剂。

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.