STING-dependent Intestinal Regeneration upon Radiation Injury

放射损伤时 STING 依赖性肠道再生

• 批准号: 10386172
• 负责人: Jian Yu
• 金额: $ 50.13万
• 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: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386172
• 关键词: 3-Dimensional; ATAC-seq; Abdomen; Acute; Adult; Bone Marrow; Cancer Patient; Cell Death; Cells; Cessation of life; Chemotherapy and/or radiation; Chronic; Coupled; DNA Damage; Data; Dissection; Dose; Dose-Limiting; Epithelial; Excision; FDA approved; FRAP1 gene; Functional disorder; Gastrointestinal Injury; Genetically Engineered Mouse; Health; Hour; Human; Image; Immune; Immune Targeting; Immune signaling; Impairment; Inflammation; Interferons; Intestines; Knowledge; LGR5 gene; Lead; Longevity; Mediating; Mitotic; Modeling; Molecular Analysis; Mucosal Immunity; Mus; Mutagens; Natural regeneration; Normal tissue morphology; Organoids; Paneth Cells; Pathway interactions; Play; Prevention; Production; Quality of life; Radiation; Radiation Injuries; Recovery; Role; Signal Transduction; Stimulator of Interferon Genes; Survivors; TP53 gene; Testing; Therapeutic; Tissues; Whole-Body Irradiation; Work; cell injury; chemokine; dysbiosis; enteritis; epigenomics; improved; in vivo; injury recovery; insight; intestinal barrier; intestinal epithelium; intestinal injury; irradiation; mouse model; novel; preservation; public health relevance; radiation recovery; receptor; repaired; response; stem cell division; stem cell niche; stem cell self renewal; stem cells; systemic inflammatory response; therapeutic target; tool; transcriptome sequencing; transcriptomics

Summary The intestinal epithelium is the fast renewing adult tissue and highly sensitive to genotoxic agents such as radiation and chemotherapy. Acute gastrointestinal (GI) injury can be lethal in radiation victims or dose-limiting in cancer patients, which can lead to chronic barrier dysfunctions that impair the quality of life in survivors. Radiation induced enteritis was first described in 1897, while there is still no FDA-approved treatment, in part due to limited understanding of how intestinal stem cell (ISC) injury is coupled to regeneration. We and others have established that the cell-intrinsic p53 pathway governs ISC intestinal regeneration using high dose total body irradiation (TBI) and abdominal irradiation (ABI) (with major bone marrow sparing) models. Our recent data indicate a novel role of “Niche” signals including innate immune signaling in intestinal regeneration. We demonstrated that a highly temporal and dynamic acute and local inflammation is “reparative”, which is activated by Stimulator of Interferon Genes (STING)-dependent Type 1 Interferon (IFN) response following delayed mitotic death to promote intestinal regeneration. Surprisingly, non-bone marrow (BM) STING plays a major role in acute crypt inflammation and regeneration. Remarkably, a single administration of IFNβ given 48 hours after TBI or ABI improved survival and intestinal regeneration in STING-deficient mice and WT mice. These data support that inducible production of IFNβ is necessary and sufficient to promote ISC and intestinal barrier recovery from radiation injury through a novel niche and immune-dependent mechanism. We will test this hypothesis with three specific aims using in vivo and ex vivo mouse and human intestinal organoids coupled with in depth mechanistic dissection. SA1. Dissect STING-dependent local IFNβ production in acute crypt regeneration. SA2. Elucidate STING-dependent immune targets for ISC regeneration. SA3. Establish IFNβ as a novel target to enhance long- term ISC and intestinal barrier recovery from radiation injury. The proposed studies will provide novel mechanistic insights in radiation-induced ISC regeneration through epithelial and immune interactions in the niche, and establish temporal STING/IFNβ signaling as a novel and normal tissue selective target to treat radiation-induced acute intestinal damage.

总结 肠上皮是快速更新的成体组织，对遗传毒性剂高度敏感， 放疗和化疗急性胃肠道（GI）损伤可能是致命的辐射受害者或剂量限制 在癌症患者中，这可能导致慢性屏障功能障碍，损害幸存者的生活质量。 放射性肠炎最早是在1897年被描述的，当时还没有FDA批准的治疗方法，部分原因是 这是由于对肠干细胞（ISC）损伤如何与再生相结合的理解有限。我们和其他人 已经建立了细胞内在p53途径控制ISC肠再生，使用高剂量的总 全身照射（TBI）和腹部照射（ABI）（保留大部分骨髓）模型。我们最近的数据 表明包括先天免疫信号在内的“小生境”信号在肠再生中的新作用。我们 证明高度暂时和动态的急性和局部炎症是“修复性的”，它被激活 通过干扰素基因刺激因子（STING）依赖性1型干扰素（IFN）反应， 促进肠道再生。令人惊讶的是，非骨髓（BM）STING在急性白血病中起主要作用。 隐窝炎症和再生。值得注意的是，在TBI或TBI后48小时给予IFNβ单次给药， ABI改善了STING缺陷小鼠和WT小鼠的存活率和肠道再生。这些数据支持 IFNβ的诱导性产生对于促进ISC和肠屏障的恢复是必要的和充分的， 辐射损伤通过一种新的生态位和免疫依赖机制。我们将用三个例子来检验这个假设。 使用体内和离体小鼠和人类肠道类器官的特定目的， 解剖SA 1.解剖急性隐窝再生中STING依赖的局部IFNβ产生。SA 2.阐明 用于ISC再生的STING依赖性免疫靶标。SA 3.建立IFNβ作为一种新的靶点， 放射损伤后肠黏膜屏障功能恢复。这些研究将提供新的 通过上皮和免疫相互作用， 生态位，并建立时间STING/IFNβ信号传导作为一种新的和正常的组织选择性靶点，以治疗 辐射引起的急性肠道损伤