Recombinant Fc Chimeras of R-spondin 1 and Slit2 for Medical Countermeasure of Chronic Radiation Syndrome

R-spondin 1 和 Slit2 的重组 Fc 嵌合体用于慢性辐射综合症的医学对策

• 批准号: 10221298
• 负责人: JIAN-GUO GENG
• 金额: $ 2.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-27 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221298
• 关键词: Acute; Adult; Agonist; Anemia; Bacteremia; Bacteria; Benchmarking; Bone Marrow; C57BL/6 Mouse; Cause of Death; Cessation of life; Chimera organism; Chronic; Cues; Data; Dose; Endotoxemia; Epithelial Cells; Exposure to; Failure; Female; Functional disorder; G-Protein-Coupled Receptors; Gastrointestinal Injury; Gastrointestinal tract structure; Half-Life; Hematopoietic stem cells; Hemorrhage; Heterozygote; Hour; Human; Infection; Injury; Intestines; LGR5 gene; Leucine-Rich Repeat; Life; Long-Term Effects; Mediating; Methods; Modeling; Monitor; Mus; Natural regeneration; Nuclear Accidents; Organ; Pharmacology; Physiologic pulse; Preventive; Proto-Oncogene Protein c-kit; Radiation; Radiation Injuries; Radiation Syndromes; Radiation Toxicity; Radiation emergency; Recombinants; Regimen; Reporting; Serum; Survival Rate; Testing; Thrombocytopenia; Tissues; Toxin; Transgenic Organisms; Whole-Body Irradiation; adult stem cell; aged; base; clinical application; cost effective; cytopenia; gastrointestinal; improved; in vivo; injury and repair; intestinal epithelium; male; medical countermeasure; mortality; mutant; organ injury; repaired; resilience; stem cells; tissue injury

Few medical countermeasures are currently available to treat chronic multi-organ failures following exposure to life-threatening radiation during radiation emergencies and nuclear disasters, especially for aged victims. Endogenous adult stem cells (ASCs), also called tissue-specific stem cells, exist, often in a scarce quantity, in almost every adult tissues and organs. However, how to robustly induce ASCs by administering soluble molecules to repair the injured organs, which could be more clinically applicable and cost-effective, remains largely unknown. We found that systemic administration of recombinant Fc chimeras of human R-spondin 1 and Slit2 (rRspo1-Fc/rSlit2-Fc) protected young mice from death, even when given 24 hours after lethal doses of whole body irradiation (WBI). Mechanistically, WBI induced the expression of Robo1 in intestinal stem cells (ISCs) and hematopoietic stem cells (HSCs). Rspo1 acted synergistically with Slit2 to enhance the survival of irradiated ISCs and HSCs and to accelerate the repair of radiation-induced acute gut and bone marrow injuries. In this proposal, we will test (1) the efficacy of rRspo1-Fc/rSlit2-Fc in mitigation of chronic radiation syndrome in young and older male and female mice, and (2) the long-term effects of rRspo1-Fc/rSlit2-Fc in irradiated young and older male and female mice. We believe that the regimen of rRspo1-Fc/rSlit2-Fc may provide a safe and effective pharmacological method to stimulate the repair of radiation-mediated chronic damage of essential tissues in aged victims.

目前，几乎没有可用的医学对策来治疗暴露于 在辐射紧急情况和核灾难期间威胁生命的辐射，特别是对老年受害者。 内源性成体干细胞(ASCs)，也称为组织特异性干细胞，通常以稀少的数量存在于 几乎每个成人的组织和器官。然而，如何通过给予可溶性物质来强健地诱导ASCs？ 修复受损器官的分子仍然存在，这可能更适用于临床，也更具成本效益 很大程度上是未知的。我们发现，全身注射重组人R-响应素1的Fc嵌合体 Slit2(rRspo1-Fc/rSlit2-Fc)即使在致死剂量后24小时给药，也能保护幼鼠免于死亡 全身照射(WBI)。WBI诱导肠干细胞表达Robo1的机制研究 (ISCs)和造血干细胞(HSCs)。Rspo1与Slit2协同作用，提高小鼠存活率 促进辐射所致的急性肠道和骨髓损伤的修复。 在这项建议中，我们将测试(1)rRspo1-FC/rSlit2-FC在缓解慢性辐射综合征方面的疗效 (2)rRspo1-Fc/rSlit2-Fc对辐射损伤小鼠的长期效应 年轻的和年长的雄性和雌性小鼠。我们认为rRspo1-Fc/rSlit2-Fc方案可以提供安全的 有效的药理学方法刺激修复辐射介导的慢性损伤的必要 老年受害者身上的组织。