LR-IL-22 for Mitigation and Management of Radiation Injuries

摘要： 减轻全身照射（TBI）或部分身体照射（PBI）造成的损害需要靶向 急性胃肠道综合征用于造血干细胞移植的放射缓解剂的肠胃外给药 综合征也可以改善胃肠道综合征;然而， 由于对肠微血管的辐射损伤而无效。我们已经证明， 施用产生并释放IL-22（LR-IL-22）的工程化罗伊氏乳杆菌， TBI诱发急性胃肠道综合征。有效缓解与LGR 5+的保存相关 肠腺干细胞及其再生能力。我们现在将建立基本机制， 通过LR-IL-22减轻辐射，并将开发具有增强的安全性和有效性的微生物治疗剂。 初步数据表明，LR-IL-22恢复辐射诱导的基因转录抑制， LGR 5+干细胞。TBI降低了肠道中芳烃受体（AhR）的表达， 产生下游产物，包括IL-22。我们假设TBI引起的肠道损伤 通过将LR-IL-22与天然诱导AhR刺激的益生菌（R2 Ic）组合， 恢复内在IL-22水平。此外，我们将确定通过我们的方法引发IL-22的释放， 工程化益生菌提高了治疗功效以及生物和环境安全性。的 第一个特异性目的测试了LR-IL-22恢复辐射抑制转录的假设， 在Lgr 5 +GFP+肠干细胞中的分子水平。第二个具体目标检验的假设是， 通过口服管饲R2 Ic进一步加强LR-IL-22对辐射减弱细胞中AhR的激活， 内源性IL-22产生。第三个具体目标涉及提供生物和 LR-IL-22的环境遏制，同时提高治疗功效。成功完成 拟议的研究将导致LR-IL-22转化为国家储备，作为一种有效的缓解剂， 急性放射性胃肠综合征

Abstract: Mitigation of damage caused by total body irradiation (TBI) or partial body irradiation (PBI) requires targeting the acute gastrointestinal syndrome. Parenteral administration of radiation mitigators for the hematopoietic syndrome may also ameliorate the gastrointestinal syndrome; however, drug delivery to the intestinal crypts is ineffective due to irradiation damage to the intestinal microvasculature. We have demonstrated that oral administration of engineered Lactobacillus reuteri, which produces and releases IL-22 (LR-IL-22), ameliorates the TBI induced acute gastrointestinal syndrome. Effective mitigation is associated with preservation of Lgr5+ intestinal crypt stem cells and their regeneration capacity. We will now establish the underlying mechanism of radiation mitigation by LR-IL-22, and will develop a microbial therapeutic with enhanced safety and efficacy. Preliminary data demonstrate that LR-IL-22 restores irradiation-induced suppression of gene transcription in Lgr5+ stem cells. TBI reduces expression of the aryl hydrocarbon receptor (AhR) in the intestine and its generation of downstream products, including IL-22. We hypothesize that TBI-induced intestinal damage will be further mitigated by combining LR-IL-22 with a probiotic (R2Ic) that naturally induces AhR to stimulate recovery of intrinsic IL-22 levels. Furthermore, we will establish that priming the release of IL-22 by our engineered probiotic increases therapeutic efficacy and the biological and environmental safety profiles. The First Specific Aim tests the hypothesis that LR-IL-22 restores radiation suppressed transcription at the molecular level in Lgr5+GFP+ intestinal stem cells. The Second Specific Aim tests the hypothesis that the activation of AhR in irradiation weakened cells by LR-IL-22 is further boosted by oral gavage of R2Ic to induce intrinsic IL-22 production. The Third Specific Aim addresses the need to provide biological and environmental containment of LR-IL-22, while improving the therapeutic efficacy. Successful completion of the proposed studies will lead to translation of LR-IL-22 to the National stockpile, as an effective mitigator of the acute radiation induced gastrointestinal syndrome.