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

项目描述：这份U01提案旨在研究辐射的病理生物学-- 诱导血管内皮细胞损伤并阐明其减弱机制 人类胃肠促生长素。放射性事故可造成严重和广泛的器官损害，其中 血管内皮细胞损伤是其中的关键组成部分。我们已经证明了从24小时开始服用Ghrelin 全身照射(TBI)后，暴露于TBI的啮齿动物存活率增加一倍。Ghrelin衰减 照射后小鼠肺和人脐静脉内皮细胞内皮细胞的活化和渗漏 (HUVEC)单层。我们第一次发现了上睑下垂，一种新的细胞死亡机制 照射小鼠肺组织和照射人脐静脉内皮细胞。新型炎症介质血清水平的研究 脑创伤小鼠冷诱导RNA结合蛋白(CIRP)升高，Ghrelin降低。什么时候 小鼠肺血管内皮细胞暴露于重组小鼠CIRP后，发生了与 NLRP3炎性小体组装和NAD(P)H氧化酶激活。Ghrelin还减少了辐射- 诱导人脐静脉内皮细胞产生活性氧。基于这些新发现，我们假设 Ghrelin通过抑制CIRP介导的EC下垂来减轻辐射引起的内皮损伤。我们 将确定Ghrelin对辐射后内皮完整性的有益影响，检查Ghrelin的影响 放射线诱导的EC下垂和CIRP的作用及Ghrelin的长期疗效评价 小鼠脑外伤后放射性内皮细胞损伤的治疗。这些拟议的研究将进一步证实 Ghrelin对血管内皮细胞辐射损伤的保护作用及建立CIRP诱导的内皮细胞下垂模型 一种新的辐射损伤机制。这些信息将支持临床前和临床 人Ghrelin作为一种新型有效的放射治疗药物的FDA批准进展 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.