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

LR-IL-22 用于减轻和管理辐射损伤

• 批准号: 10569299
• 负责人: JOEL S GREENBERGER
• 金额: $ 56.02万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-20 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569299
• 关键词: ARNT gene; Acute; Address; Adhesions; Anatomy; Aryl Hydrocarbon Receptor; Bacteria; Biological; Biological Containment; Blood Vessels; Cell Death; Cells; Chemotactic Factors; Chromosomes; Containment; Cytolysis; Data; Drug Delivery Systems; Effectiveness; Engineered Probiotics; Engineering; Environment; Gastrointestinal tract structure; Generations; Genes; Genetic Transcription; Goals; Hematopoietic; In Vitro; Intestines; LGR5 gene; Lactobacillus reuteri; Lymphocyte; Lymphoid Cell; Marrow; Measures; Mediating; Molecular; Molecular Mechanisms of Action; Mus; Natural regeneration; Oral; Oral Administration; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmids; Probiotics; Production; Property; Proteins; Radiation; Radiation Injuries; Radiation induced damage; Recombinants; Recovery; Regenerative capacity; Role; Safety; Signal Pathway; Syndrome; Testing; Therapeutic; Translations; Treatment Efficacy; Whole-Body Irradiation; Wild Type Mouse; cell injury; clinical application; experimental study; gastrointestinal; gut microbiota; improved; inducible Cre; interleukin-22; intestinal crypt; irradiation; microbial; mutant; novel; parenteral administration; preservation; prevent; radiation countermeasure; radiation mitigation; radiation mitigator; recruit; response; safety engineering; stem cell niche; stem cells; transcriptome sequencing; γδ T cells

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.

抽象的： 由全身照射（TBI）或部分身体照射（PBI）造成的减轻损害需要针对目标 急性胃肠道综合征。造血的肠胃外辐射缓解剂 综合征还可以改善胃肠道综合征；但是，将药物输送到肠道隐窝为 由于对肠道微脉管系统的辐照损害而无效。我们已经证明了口头 产生和释放IL-22（LR-IL-22）的工程乳酸杆菌疗法的给药可改善 TBI诱导急性胃肠道综合征。有效缓解与保存LGR5+有关 肠道隐窝干细胞及其再生能力。我们现在将建立的基本机制 LR-IL-22缓解辐射，并将开发具有增强安全性和功效的微生物治疗性。 初步数据表明，LR-IL-22恢复了辐照诱导的基因转录抑制 LGR5+干细胞。 TBI降低了肠内芳基烃受体（AHR）的表达 下游产品的产生，包括IL-22。我们假设TBI引起的肠道损伤将 通过将LR-IL-22与益生菌（R2IC）结合起来，从而进一步缓解，该益生菌（R2IC）自然诱导AHR刺激 恢复固有的IL-22水平。此外，我们将确定我们的IL-22释放 工程益生菌提高了治疗功效以及生物学和环境安全概况。这 第一个特定目的检验了LR-IL-22恢复辐射抑制转录的假设 LGR5+ GFP+肠干细胞中的分子水平。第二个特定目的检验了以下假设 通过口服R2IC，通过LR-IL-22激活LR-IL-22的AHR通过LR-IL-22的削弱细胞激活，以诱导 固有的IL-22产生。第三个特定目的解决了提供生物学和 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转换为国家库存，作为有效的减轻者 急性辐射诱导的胃肠道综合征。