STING-dependent Intestinal Regeneration upon Radiation Injury

摘要 肠上皮是快速更新的成体组织，对遗传毒性物质高度敏感，如 放疗和化疗。急性胃肠道(GI)损伤对辐射受害者或剂量限制可能是致命的 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。 放射性肠炎于1897年首次被描述，当时仍没有FDA批准的部分治疗方法。 由于对肠道干细胞(ISC)损伤与再生的关系了解有限。我们和其他人 已确定细胞内固有的P53途径使用高剂量TALL来管理ISC肠道再生 全身照射(TBI)和腹部照射(ABI)(主要保留骨髓)模型。我们最近的数据 表明了包括先天免疫信号在内的“小众”信号在肠道再生中的新作用。我们 证明高度暂时和动态的急性和局部炎症是“修复性的”，被激活 由干扰素基因刺激物(STING)依赖的1型干扰素(IFN)对延迟有丝分裂的反应 死亡能促进肠道再生。令人惊讶的是，非骨髓(BM)叮咬在急性 隐窝发炎和再生。值得注意的是，脑损伤后48小时单次注射干扰素β或 ABI改善了刺痛缺陷小鼠和WT小鼠的存活率和肠道再生。这些数据支持 诱导性干扰素β的产生是促进肠系膜上皮细胞癌和肠屏障恢复的必要条件和充分条件。 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一假设 利用体内和体外小鼠和人肠道有机化合物结合深度机制的特定靶点 解剖。SA1.解剖急性隐窝再生过程中局部刺痛依赖的干扰素β产生。SA2.阐明 依赖刺的免疫靶点用于ISC再生。SA3.建立干扰素β作为新的靶点以增强长效 放射性损伤后的ISC和肠屏障恢复。拟议的研究将提供新的 辐射通过上皮和免疫相互作用诱导间质干细胞再生的机制研究 并建立了颞部刺痛/干扰素β信号作为一种新的正常组织选择性靶点进行治疗 辐射引起的急性肠道损伤。

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.