Radiation injury to the heart

辐射对心脏的损伤

• 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
• 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

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

本应用的目的是了解全身照射(TBI)导致冠状动脉硬化和心功能障碍的机制，并确定和开发减轻和/或治疗此类损伤的医学对策。我们的初步研究表明，与放射性恐怖袭击和核事故有关的剂量和时间表的10Gy单次照射与心血管疾病、冠状动脉硬化症和心脏功能损伤的危险因素的发展有关。此外，药物氯沙坦和营养姜黄素似乎可以防止脑损伤导致的心血管疾病危险因素的发展。虽然有大量关于脑外伤对肠道和肾脏等器官的影响的文献，但还没有关于脑外伤导致心脏损伤的机制的信息。导致脑外伤后冠状动脉硬化和心功能不全的分子和细胞事件的顺序尚不清楚。我们假设，脑外伤对心脏的损害是由于心血管疾病风险因素增加所致。这一假设的推论是，减少心血管疾病危险因素的药物治疗将在治疗脑损伤引起的冠状动脉硬化和心功能不全方面有效。这一假设将在已建立的大鼠骨髓移植模型中得到验证。将测试三个特定目标：特定目标1将确定TBI导致血管系统促凝剂和抗凝血剂功能失衡的程度，从而导致冠状动脉硬化和心功能障碍。特异靶2将确定TBI间接损伤冠状动脉血管/内皮细胞以减少一氧化氮和增加一氧化氮合酶产生超氧化物歧化酶的机制。具体目标3将确定医疗对策的能力，以减轻或治疗在辐射暴露后给予脑损伤对心血管系统的损伤。这些研究将确定脑照射对冠状动脉血管和心功能损伤的潜在机制，并确定现有药物对策缓解和/或治疗辐射引起的心血管系统损伤的能力。 1