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

LR-IL-22 用于减轻和管理辐射损伤

基本信息

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
项目类别：
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

项目摘要

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：减轻全身照射 (TBI) 或部分身体照射 (PBI) 造成的损伤需要靶向治疗急性胃肠道综合症。用于造血功能的放射缓解剂的胃肠外给药综合征还可能改善胃肠道综合征；然而，药物输送到肠隐窝是由于辐射损伤肠道微血管而无效。我们已经证明，口头施用工程化罗伊氏乳杆菌可产生并释放 IL-22 (LR-IL-22)，可改善 TBI诱发急性胃肠道综合征。有效的缓解措施与 Lgr5+ 的保存有关肠隐窝干细胞及其再生能力。我们现在要建立底层机制通过 LR-IL-22 缓解辐射，并将开发一种安全性和有效性更高的微生物疗法。初步数据表明，LR-IL-22 可恢复辐射诱导的基因转录抑制 Lgr5+ 干细胞。 TBI 降低肠道中芳烃受体 (AhR) 的表达及其产生下游产品，包括 IL-22。我们假设 TBI 引起的肠道损伤将通过将 LR-IL-22 与自然诱导 AhR 刺激的益生菌 (R2Ic) 结合，可进一步缓解内在IL-22水平的恢复。此外，我们将确定通过我们的方法启动 IL-22 的释放工程益生菌可提高治疗功效以及生物和环境安全性。这第一个具体目标测试了 LR-IL-22 恢复辐射抑制转录的假设 Lgr5+GFP+肠干细胞的分子水平。第二个具体目标检验了以下假设：口服 R2Ic 进一步增强 LR-IL-22 对辐射减弱细胞中 AhR 的激活，从而诱导内在的 IL-22 产生。第三个具体目标解决了提供生物和 LR-IL-22的环境遏制，同时提高治疗效果。圆满完成了拟议的研究将导致 LR-IL-22 转化为国家储备，作为一种有效的缓解剂急性辐射引起的胃肠道综合症。