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：
10614233
负责人：
Max Brenner
金额：
$ 10万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614233
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 Endothelium 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 Injury Kidney Kinetics Knock-out Liver Long-Term Effects Lung Mediating Monitor Mus Organ Organ failure Oxidases Pathway interactions Permeability Production RNA-Binding Proteins Radiation Radiation Accidents Radiation Dose Unit Radiation Injuries Radiation Toxicity Radiation exposure 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 Vascular Endothelial Growth Factors Western Blotting Whole-Body Irradiation Wild Type Mouse antagonist attenuation base body system cell injury clinical development density effective therapy endothelial regeneration gastrointestinal system ghrelin ghrelin receptor improved in vivo in vivo imaging system irradiation medical countermeasure 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，并阐明了导致其衰减的机制人类生长素。放射事件可能会造成严重和广泛的器官损害，其中内皮损伤是关键组成部分。我们已经证明了生长素释放释放从24小时开始总体照射后（TBI）使暴露于TBI的啮齿动物的存活率增加了一倍。 Ghrelin衰减辐照小鼠肺和辐照的人脐静脉EC中的内皮激活和渗漏（HUVEC）单层。我们第一次在暴露于TBI和受辐照的HUVEC的小鼠的肺。新型炎症介质的血清水平在TBI小鼠中升高了可冷诱导的RNA结合蛋白（CIRP），并通过生长素释放。什么时候暴露于重组鼠CIRP，小鼠肺血管ECS经历了与 NLRP3炎性体组装和NAD（P）H氧化酶活性。生长素蛋白也恶化了辐射诱导HUVEC中活性氧的产生。基于这些新颖的发现，我们假设该生长素蛋白通过抑制CIRP介导的EC凋亡来减轻辐射诱导的内皮损伤。我们将在辐照后确定生长素对内皮完整性的有益作用在辐射引起的EC凋亡和CIRP的作用上，并评估生长素素的长期作用 TBI后对辐射诱导的EC损伤进行治疗。这些提出的研究将进一步确认 Ghrelin对血管EC的辐射损伤的有益作用，并建立CIRP诱导的EC凋亡为辐射引起的损伤的新型机制。此信息将支持临床前和临床开发人类生长素释放其FDA批准为一种新颖有效的辐射医学对策。