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

摘要： 减轻全身照射(TBI)或局部照射(PBI)造成的损害需要靶向 急性胃肠道综合症。血液系统放射减少剂的肠外给药 综合征也可以改善胃肠道综合征；然而，向肠道隐窝输送药物是 因辐射损伤肠道微血管而无效。我们已经证明了口述 服用能产生和释放IL-22(LR-IL-22)的工程雷氏乳杆菌可以改善 颅脑损伤致急性胃肠道综合征。有效的缓解与Lgr5+的保存有关 肠隐窝干细胞及其再生能力。我们现在将建立 通过LR-IL-22减轻辐射，并将开发一种具有更高安全性和有效性的微生物疗法。 初步数据显示，LR-IL-22可恢复辐射诱导的基因转录抑制 LGr5+干细胞。脑损伤减少肠道芳香烃受体(AhR)的表达 产生下游产品，包括IL-22。我们推测，脑外伤引起的肠道损伤将 通过将LR-IL-22与一种天然诱导AhR刺激的益生菌(R2Ic)结合来进一步缓解 恢复固有的IL-22水平。此外，我们将确定，通过我们的 经过改造的益生菌提高了治疗效果以及生物和环境安全性。这个 第一个特定目的是验证这样的假设，即LR-IL-22恢复辐射抑制的转录在 Lgr5+GFP+肠干细胞的分子水平。第二个具体目标是检验这样一个假设： 口服R2Ic可进一步增强LR-IL-22对辐射损伤细胞AhR的激活作用 内源性IL-22的产生。第三个具体目标是解决需要提供生物和 在环境中遏制LR-IL-22，同时提高治疗效果。圆满完成 拟议的研究将导致将LR-IL-22转化为国家储备，作为有效的缓解 急性辐射引起的胃肠道综合征。

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.