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.

概括 肠上皮是快速更新的成人组织，对遗传毒性剂（例如 放射和化学疗法。急性胃肠道（GI）损伤在辐射滥用或限制剂量上可能是致命的 在癌症患者中，可能导致慢性屏障功能障碍，从而损害幸存者的生活质量。 辐射诱导的肠炎于1897年首次描述，而仍然没有FDA批准的治疗 由于对肠道干细胞（ISC）损伤如何与再生的了解有限。我们和其他人 已经确定细胞内p53途径使用高剂量总数控制ISC肠再生 人体辐照（TBI）和腹部照射（ABI）（具有主要的骨髓支撑）模型。我们最近的数据 表明包括先天免疫信号传导在肠道再生中的“利基”信号的新作用。我们 证明高度暂时和动态的急性和局部炎症是“修复”，它被激活 通过干扰素基因（sting）依赖性类型1个干扰素（IFN）响应的刺激剂后有丝分裂后反应 死亡以促进肠道再生。令人惊讶的是，非骨髓（BM）刺在急性中起着重要作用 地穴注射和再生。值得注意的是，在TBI或TBI或 ABI改善了缺乏刺激的小鼠和WT小鼠的生存和肠再生。这些数据支持 IFNβ的可诱导产生是必要的，足以促进ISC和从 通过新颖的利基和免疫依赖机制进行辐射损伤。我们将用三个 使用体内和离体小鼠和人肠癌的特定目的与深度机械 解剖。 SA1。在急性隐窝再生中剖析了依赖于STING的局部IFNβ的局部IFNβ。 SA2。阐发 ISC再生的sting依赖性免疫靶标。 SA3。建立IFNβ作为增强长期目标的新目标 术语ISC和从辐射损伤中恢复的肠道屏障。拟议的研究将提供新颖 通过上皮和免疫学相互作用在辐射引起的ISC再生中的机械见解 利基市场，并建立临时刺痛/IFNβ信号作为一种新型和正常组织选择性靶标 辐射引起的急性肠道损伤。