Intense Light Therapy for Perioperative Cardio-Protection

围术期心脏保护的强光治疗

• 批准号: 9031802
• 负责人: Tobias Eckle
• 金额: $ 38.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031802
• 关键词: Accounting; Acute myocardial infarction; Address; Age; Anticoagulation; Area; Attenuated; Blood; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cessation of life; Circadian Rhythms; Clinical Research; Data; Dose; Epidemiologic Studies; Funding; Goals; Health; Healthcare; Hemorrhage; Hospitals; Hour; Human; Human Volunteers; In Situ; Injury; Intervention; Investigation; Ischemia; Kinetics; Label; Light; Mediating; Melatonin; Metabolic Pathway; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardial tissue; Myocardium; Operative Surgical Procedures; Patients; Perioperative; Peripheral; Pharmaceutical Preparations; Phototherapy; Platelet Inhibitors; Population; Postoperative Period; Predisposition; Proteins; Reperfusion Therapy; Research Proposals; Resistance; Risk; Saliva; Sampling; Site; Source; Specificity; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcript; Troponin I; United States; anaerobic glycolysis; base; blind; care burden; defined contribution; design; high risk; in vivo; mortality; myocardial infarct sizing; novel; novel therapeutics; percutaneous coronary intervention; prevent

 DESCRIPTION (provided by applicant): Acute myocardial infarction is among the most important predictors of perioperative short- and long-term morbidity and mortality in surgical patients. As our population ages, more high-risk cardiac patients will undergo surgery, and perioperative myocardial infarction is very likely to be an increasing problem. Current therapeutic interventions such as percutaneous coronary intervention in combination with anticoagulation and platelet inhibitors, however, may not be suitable in the perioperative setting due to the risk of bleeding from the surgical site. Therefore additional therapeutic approaches that would render the myocardium more resistant to ischemia and attenuate myocardial reperfusion injury are an intense area of investigation. Epidemiologic studies in humans indicate that susceptibility to ischemic myocardial tissue injury is time-of-the-day dependent, with more severe injury occurring in the early morning hours after a longer period without daylight. To address the possibility that light-exposure could function to attenuate ischemic myocardial injury, we pre-treated mice for different periods with intense light. Surprisingly, we observed a time-dependent reduction in myocardial infarct size and troponin I release following light treatment. A search for light inducible circadian rhythm proteins revealed a robust induction of cardiac Period 2 (Per2) protein levels upon intense light exposure. Proof-of-principle studies showed that light mediated cardio-protection or Per2 induction was abolished in mice lacking the Per2 protein or mice without the ability to sense light, respectively. Based on these findings, we hypothesize that intense light therapy provides robust cardio- protection by stabilizing cardiac Per2, thereby leading to concomitant cardio-protection from ischemia. To address this hypothesis, we designed three specific aims: 1. Define the dose, timing, and tissue specific source for light-elicited Per2 stabilization and cardio-protection, 2. Study molecular mechanisms of how light therapy functions to provide cardio-protection from ischemia and reperfusion, 3. Elucidate the influence of intense light therapy on the stabilization of PER2 protein in humans. The long-term goal of our studies is to introduce intense light therapy into the hospital to preven or treat myocardial injury in surgical patients, the most common cause of postoperative morbidity and mortality. We anticipate that successful completion of our Aims will allow us to initiate a clinical study on pre-operative intense light therapy in surgical patients towards the ed of the funding period.

 描述（由适用提供）：急性心肌梗塞是手术患者周期性短期和长期发病率和死亡率的最重要预测指标之一。随着人口年龄的增长，更多的高风险心脏患者将散发性，周期性心肌梗塞很可能是一个越来越多的问题。然而，当前的治疗干预措施，例如经皮冠状动脉干预与抗凝作用和血小板抑制剂结合使用，由于外科手术部位出血的风险，在周期性环境中可能不适合。因此，其他治疗方法将使心肌对缺血性更具耐药性并减轻心肌再灌注损伤是一个强烈的投资领域。人类的流行病学研究表明，对脑部心肌组织损伤的敏感性是当天的依赖性，在没有白天的时间更长的时间后清晨发生了更严重的损伤。为了解决光曝光可能功能减弱缺血性心肌损伤的可能性，我们以强光预先治疗的小鼠预处理小鼠。令人惊讶的是，我们观察到轻度处理后，心肌基础设施大小和肌钙蛋白I释放的时间依赖性减少。搜索光诱导的昼夜节律蛋白显示出强烈的光照暴露后心脏周期2（PER2）蛋白水平的强烈诱导。原理证明的研究表明，在缺乏PER2蛋白或小鼠的小鼠中，光介导的有心脏保护或PER2诱导分别没有能力。基于这些发现， 我们假设强烈的光疗法通过稳定心脏PER2提供了强大的心脏保护，从而导致缺血的心脏保护。为了解决这一假设，我们设计了三个特定的目的：1。定义光吸收的PER2稳定和心脏保护的剂量，时间和组织特异性来源，2。研究光治疗功能如何提供缺血性和重复的心脏保护作用的分子机制。我们研究的长期目标是将强烈的光治疗引入医院，以预防或治疗外科患者的心肌损伤，这是术后发病率和死亡率的最常见原因。我们预计，成功完成我们的目标将使我们能够针对手术患者进行临床研究，以实现手术患者的术前疗法疗法。