Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction

项目描述：本U 01提案旨在研究辐射的病理生物学- 诱导的血管内皮细胞（EC）损伤，并阐明其衰减的机制， 人胃饥饿素放射性事故可造成严重和广泛的器官损伤，其中 内皮损伤是一个关键因素。我们已经证明，从24小时开始给予胃饥饿素， 全身照射（TBI）后，暴露于TBI的啮齿动物的存活率增加了一倍。减毒胃饥饿素 照射小鼠肺和照射人脐静脉EC中的内皮活化和渗漏 （HUVEC）单层。这是我们第一次发现细胞凋亡，一种新的细胞死亡机制， 暴露于TBI的小鼠肺和经辐照的HUVEC中。新型炎症介质的血清水平 冷诱导的RNA结合蛋白（CIRP）在TBI小鼠中升高，而ghrelin降低。当 暴露于重组鼠CIRP，小鼠肺血管EC发生与CIRP相关的焦亡， NLRP 3炎性小体组装和NAD（P）H氧化酶活化。Ghrelin还能减少辐射- 诱导HUVEC中活性氧的产生。基于这些新发现，我们假设 Ghrelin通过抑制CIRP介导的EC凋亡减轻辐射诱导的内皮损伤。我们 将确定ghrelin对辐射后内皮完整性的有益作用， 对辐射诱导的EC热凋亡和CIRP的作用，并评估生长激素释放肽的长期影响 治疗对TBI后小鼠中辐射诱导的EC损伤的影响。这些研究将进一步证实 Ghrelin对血管内皮细胞辐射损伤的有益作用，并建立CIRP诱导的内皮细胞热凋亡， 辐射损伤的新机制。这些信息将支持临床前和临床 人生长激素释放肽的开发，其FDA批准作为一种新的和有效的放射医疗 对策

PROJECT DESCRIPTION: This U01 proposal is intended to investigate the pathobiology of radiation- induced vascular endothelial cell (EC) injury and elucidate the mechanisms responsible for its attenuation by human ghrelin. Radiological incidents can cause severe and widespread organ damage, of which endothelial injury is a key component. We have demonstrated that ghrelin administration starting at 24 h after total body irradiation (TBI) doubled the survival rate of rodents exposed to TBI. Ghrelin attenuated endothelial activation and leakage in the lungs of irradiated mice and in irradiated human umbilical vein EC (HUVEC) monolayers. For the first time, we discovered pyroptosis, a new mechanism of cell death, in the lungs of mice exposed to TBI and in irradiated HUVECs. Serum levels of the novel inflammatory mediator cold-inducible RNA-binding protein (CIRP) were elevated in TBI mice and reduced by ghrelin. When exposed to recombinant murine CIRP, mouse lung vascular ECs underwent pyroptosis associated with NLRP3 inflammasome assembly and NAD(P)H oxidase activation. Ghrelin also decreased radiation- induced production of reactive oxygen species in HUVECs. Based on these novel findings, we hypothesize that ghrelin mitigates radiation-induced endothelial injury by inhibiting CIRP-mediated EC pyroptosis. We will determine ghrelin’s beneficial effects on endothelial integrity after irradiation, examine ghrelin’s effects on radiation-induced EC pyroptosis and the role of CIRP, and evaluate the long-term effects of ghrelin treatment on radiation-induced EC injury in mice after TBI. These proposed studies will further confirm ghrelin’s beneficial effects on radiation injury to vascular ECs and establish CIRP-induced EC pyroptosis as a novel mechanism of radiation-induced injury. This information will support the preclinical and clinical development of human ghrelin towards its FDA approval as a novel and effective radiation medical countermeasure.