权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：本U01提案旨在研究辐射-的病理生物学