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

辐射引起的血管内皮细胞损伤的机制及其纠正

基本信息

批准号：
9391119
负责人：
PING WANG
金额：
$ 57.52万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-07 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9391119
关键词：
Amino Acids Attenuated Blood Vessels Cardiovascular system Cell Adhesion Molecules Cell Death Cells Clinical Complex Detection Development Dose Dyes Endocrine system Endothelial Cells Enzyme-Linked Immunosorbent Assay Evans blue stain Exposure to Extravasation FDA approved Fibrosis Flow Cytometry Functional disorder Granulocyte Colony-Stimulating Factor Hematopoietic Histology Human Immune system Immunofluorescence Immunologic In Vitro Incubated Inflammasome Inflammation Mediators Injectable Injury Kidney Kinetics Knock-out Liver Long-Term Effects Lung Mediating Medical Monitor Mus Natural regeneration Organ Organ failure Oxidases Pathway interactions Permeability Production RNA-Binding Proteins Radiation Radiation Injuries Radiation Toxicity Radiation exposure Radiology Specialty Reactive Oxygen Species Recombinants Recovery Reporting Rodent Role Safety Serum Signal Transduction Specificity Survival Rate Tight Junctions Time TimeLine Trichrome stain method Umbilical vein Vascular Endothelial Cell Western Blotting Whole-Body Irradiation Wild Type Mouse attenuation base body system cell injury clinical development density effective therapy gastrointestinal system ghrelin ghrelin receptor improved in vivo in vivo imaging system irradiation monolayer mortality neutralizing antibody novel peptide hormone preclinical development public health relevance radiation-induced injury receptor subcutaneous

项目摘要

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.

项目描述：该 U01 提案旨在研究辐射的病理学- 诱导血管内皮细胞（EC）损伤并阐明其减弱机制人类生长素释放肽事件可造成严重且广泛的器官损伤，其中内皮损伤是一个关键组成部分，我们已经证明从 24 小时开始施用 ghrelin。全身照射（TBI）后，暴露于 Ghrelin 的啮齿动物的存活率增加了一倍。受辐射小鼠肺和受辐射人脐静脉 EC 中的内皮活化和渗漏（HUVEC）单层细胞中，我们首次发现了细胞焦亡（pyroptosis），这是一种新的细胞死亡机制。暴露于 TBI 的小鼠肺部和受辐射的 HUVEC 中新型炎症介质的血清水平。 TBI 小鼠中冷诱导 RNA 结合蛋白 (CIRP) 升高，而胃饥饿素则降低。暴露于重组小鼠 CIRP 下，小鼠肺血管 EC 发生细胞焦亡 NLRP3 炎症小体组装和 NAD(P)H 氧化酶激活也减少了辐射。基于这些新发现，我们探索了 HUVEC 中活性氧的诱导产生。 ghrelin 通过抑制 CIRP 介导的 EC 焦亡来减轻辐射引起的内皮损伤。将确定 ghrelin 在照射后对内皮完整性的有益影响，检查 ghrelin 的作用对辐射诱导的 EC 焦亡和 CIRP 的作用的影响，并评估 ghrelin 的长期影响这些拟议的研究将进一步证实 TBI 后小鼠辐射引起的 EC 损伤的治疗。 ghrelin 对血管 EC 辐射损伤的有益作用，并将 CIRP 诱导的 EC 焦亡确定为辐射诱发损伤的新机制该信息将支持临床前和临床。人类生长素释放肽的开发有望获得 FDA 批准作为一种新型有效的放射药物对策。