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Endothelial Dysfunction in Radiation-induced Lung and Heart Toxicity

辐射引起的肺和心脏毒性中的内皮功能障碍

基本信息

批准号：
9385357
负责人：
ROSS B MIKKELSEN
金额：
$ 42.49万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385357
关键词：
Abbreviations Adhesions Animals Automobile Driving Biological Assay Biological Availability Biological Markers Breathing CCL2 gene CD44 gene Carbon Monoxide Cardiac Catheterization Cell Cycle Arrest Cells Chest Chronic Clinic Clinical Treatment Clinical Trials Coupling Creatine Kinase Cyclic GMP-Dependent Protein Kinases DHFR gene Dihydrofolate Reductase Doppler Echocardiography Dose Electrocardiogram Endothelial Cells Enzymes Event Fibroblasts Fibrosis Frequencies Functional disorder GTP Cyclohydrolase Heart Hematopoietic Hemin Hour Human In Vitro Infiltration Inflammation Inflammatory Injection of therapeutic agent Injury Insulin-Like-Growth Factor I Receptor Interleukin-1 Interleukin-13 Interleukin-6 Ionizing radiation Late Effects Left Lung Mass Spectrum Analysis Measurement Measures Mesenchymal Metabolic Mitochondria Mus NADPH Oxidase Nitric Oxide Nitric Oxide Synthase Normal tissue morphology Nuclear Oral Administration Oxidoreductase Pathway interactions Patients Peroxonitrite Plasma Platelet-Derived Growth Factor Process Proteins Protocols documentation Quantitative Reverse Transcriptase PCR RNA Interference Radiation Radiation exposure Radiation therapy Relaxation Reverse Transcription Role Sampling Source Superoxides Syndrome TP53 gene Tail Testing Time Tissues Toxic effect Transforming Growth Factor beta Transforming Growth Factors Translating Vascular Diseases Veins Ventricular Whole-Body Irradiation Wound Healing arginase ataxia telangiectasia mutated protein beta-Galactosidase cytokine dihydropteridine reductase driving force endothelial dysfunction exosome experimental study heme oxygenase-1 hemodynamics improved inflammatory marker intercellular cell adhesion molecule lung injury malignant breast neoplasm oxidation potential biomarker prevent radiation effect senescence sepiapterin tetrahydrobiopterin therapeutic evaluation transcription factor

项目摘要

This proposal will test the hypothesis that radiation-induced late lung and heart toxicities are a consequence of endothelial dysfunction defined as uncoupled nitric oxide synthetase activity and decreased nitric oxide bioavailability establishing a state of chronic inflammation driving a persistent pro-fibrotic process associated with abnormal wound repair and late normal tissue injury. For radiation a sub-lethal dose that induces the hematopoietic syndrome (5 Gy) immediately followed by thorax only “top-up” of 6.5 Gy will be used as the radiation protocol. The proposal will test whether sepiapterin, a metabolic precursor of tetrahydrobiopterin, or induction of the inflammatory protein, heme oxygenase-1, 24 hours post IR re-establishes a normal wound repair mechanism removing the driving force for chronic inflammation and fibrosis. The proposed experiments also test whether exosomes shed from irradiated endothelial cells provide potential biomarkers for the late effects of radiation. AIM 1 Hypothesis: radiation uncouples nitric oxide synthetase activity by reducing tetrahydrobiopterin in cardiac and lung endothelial cells in vitro and this results endothelial cell dysfunction as evaluated by markers of inflammation, senescence and endothelial-mesenchymal transition. AIM 2 Hypothesis: oral administration of sepiapterin or induction of heme oxygenase-1 expression with hemin 24 hours after a radiation exposure, enhances lung and cardiac function as evidenced by decreased breathing frequency, decreased inflammation, enhanced contractile reserve, improved relaxation and diastolic function, reduced fibrosis and enhanced survival. AIM 3 Hypothesis: exosomes and their cargo purified from the plasma of irradiated mice in Aim 2 and from the plasma of patients treated by radiotherapy for lung and breast cancer stimulate endothelial cell dysfunction and represent a potential source of biomarkers for lung and cardiac injury following radiation.

这一提议将验证一种假设，即辐射引起的晚期肺和心脏毒性是