Radiation injury to the heart

辐射对心脏的损伤

基本信息

批准号：
7933894
负责人：
JOHN E BAKER
金额：
$ 38万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-22 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7933894
关键词：
Angiotensin II Receptor Anticoagulants Blood Pressure Bone Marrow Transplantation Captopril Cardiac Cardiovascular Diseases Cardiovascular system Chest Co-Immunoprecipitations Collagen Coronary Curcumin Development Dose Drug usage Echocardiography Effectiveness Endothelium Event Fibrosis Functional disorder Heart Heat shock proteins Histology Hyperlipidemia Hypertension Injury Injury to Kidney Intestines Kidney Lipids Literature Liver Losartan Measurement Mediating Medical Modeling Molecular Molecular Biology Techniques NOS3 gene Nitric Oxide Nitric Oxide Synthase Nitrites Nuclear Accidents Organ PAR-1 Receptor Pharmacologic Substance Phosphorylation Pravastatin Production Radiation Radiation Injuries Rattus Risk Factors Role Schedule Sclerosis Serine Simvastatin Superoxides Testing Thrombin Receptor Thrombopoietin Time Ventricular Ventricular Dysfunction Ventricular Function Whole-Body Irradiation X-Ray Computed Tomography effective therapy injured irradiation prevent response

项目摘要

The objective of this application is to understand the mechanisms responsible for coronary sclerosis and cardiac dysfunction induced by total body irradiation (TBI), and to identify and develop medical countermeasures to mitigate and/or treat such injury. Our preliminary studies indicate that 10 Gy single-dose TBI, a dose and schedule relevant to radiological terrorist attacks and nuclear accidents, is associated with the development of risk factors for cardiovascular disease, coronary sclerosis and functional injury to the heart. Furthermore, the pharmaceutical Losartan and the nutriceutical curcumin appear to prevent TBI-induced development of risk factors for cardiovascular disease. Whereas there is a substantial body of literature regarding the impact of TBI in organs such as the intestine and kidney, there is no information about the mechanisms by which TBI causes injury to the heart. The sequence of the molecular and cellular events that result in coronary sclerosis and ventricular dysfunction following TBI is not known. We hypothesize that TBI-induced damage to the heart results from increased risk factors for cardiovascular disease. The corollary to this hypothesis is that pharmaceutical treatments that decrease risk factors for cardiovascular disease will be effective in treating TBI-induced coronary sclerosis and ventricular dysfunction. This hypothesis will be tested in an established rat bone marrow transplant model. Three specific aims will be tested: Specific Aim 1 will determine the extent that TBI results in an imbalance between procoagulant and anticoagulant function of the vasculature resulting in coronary sclerosis and ventricular dysfunction. Specific Aim 2 will determine the mechanisms by which TBI indirectly injures the coronary vasculature/endothelium to decrease nitric oxide and increases superoxide production from nitric oxide synthase. Specific Aim 3 will determine the ability of a medical countermeasure to mitigate or treat TBI induced injury to the cardiovascular system when given after radiation exposure. These studies will define mechanisms underlying TBIinduced injury to the coronary vasculature and ventricular function and determine the ability of existing pharmaceuticals countermeasures to mitigate and/or treat radiation-induced injury to the cardiovascular system. 1

该应用的目的是了解负责全身照射（TBI）引起的冠状硬化和心脏功能障碍的机制，并识别和发展医学对策以减轻和/或治疗这种损伤。我们的初步研究表明，与放射性恐怖袭击和核事故有关的10 Gy单剂量TBI与心血管疾病，冠状动脉硬化和对心脏功能损伤的危险因素有关。此外，药物氯沙坦和营养姜黄素似乎可以防止TBI引起的心血管疾病危险因素的发展。关于TBI在肠道和肾脏等器官中的影响，有大量文献，但没有关于TBI对心脏造成伤害的机制的信息。 TBI后导致冠状硬化和心室功能障碍的分子和细胞事件的序列尚不清楚。我们假设TBI引起的心脏疾病风险因素增加导致心脏损害。这一假设的推论是，降低心血管疾病危险因素的药物治疗将有效治疗TBI诱导的冠状硬化症和心室功能障碍。该假设将在已建立的大鼠骨髓移植模型中进行检验。将测试三个具体目标：具体目标1将确定TBI导致脉管系统的凝血和抗凝功能之间的不平衡，导致冠状硬化和心室功能障碍。特定的目标2将确定TBI间接损害冠状动脉脉管系统/内皮以减少一氧化氮并增加一氧化氮合酶产生的超氧化物的机制。特定的目标3将确定医疗对策在辐射暴露后给予减轻或治疗TBI诱导心血管系统损伤的能力。这些研究将定义TBI诱导的冠状动脉血管和心室功能的损伤的机制，并确定现有药物对抗减轻和/或治疗心血管系统辐射诱导的损伤的能力。 1