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