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

目前几乎没有医疗对策可用于治疗暴露于以下物质后的慢性多器官衰竭： 在辐射紧急情况和核灾难期间，特别是对老年受害者，威胁生命的辐射。 内源性成体干细胞（ASC），也称为组织特异性干细胞，存在于组织中，通常数量稀少， 几乎所有的成人组织和器官。然而，如何通过施用可溶性的药物来稳健地诱导ASC， 修复受损器官的分子，这可能是更临床应用和成本效益，仍然存在 大部分未知。我们发现，系统给予人R-spondin 1的重组Fc嵌合体， 和Slit 2（rRspo 1-Fc/rSlit 2-Fc）保护幼龄小鼠免于死亡，即使在致死剂量后24小时给予 全身照射（WBI）WBI诱导肠干细胞中Robo 1的表达 造血干细胞（HSC）是指造血干细胞（ISC）和造血干细胞（HSC）。Rspo 1与Slit 2协同作用， 辐射的ISCs和HSC，并加速辐射诱导的急性肠道和骨髓损伤的修复。 在本提案中，我们将测试（1）rRspo 1-Fc/rSlit 2-Fc在缓解慢性辐射综合征中的功效 在年轻和年长的雄性和雌性小鼠中，以及（2）rRspo 1-Fc/rSlit 2-Fc在辐射的小鼠中的长期作用。 年轻和年长的雄性和雌性小鼠。我们认为rRspo 1-Fc/rSlit 2-Fc方案可以提供安全的 和有效的药理学方法，以刺激修复辐射介导的慢性损伤的基本 老年受害者的组织

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.