Intense Light Therapy for Perioperative Cardio-Protection

 描述(申请人提供)：急性心肌梗死是外科患者围手术期短期和长期发病率和死亡率最重要的预测因子之一。随着人口老龄化，更多的高危心脏病患者将接受手术，围手术期心肌梗死很可能成为一个日益严重的问题。然而，目前的治疗干预措施，如经皮冠状动脉介入结合抗凝和血小板抑制剂，可能不适合围手术期环境，因为手术部位有出血的风险。因此，其他治疗方法将使心肌对缺血更具抵抗力，并减轻心肌再灌注损伤，是一个激烈的研究领域。在人类中的流行病学研究表明，对缺血性心肌组织损伤的易感性与一天中的时间有关，更严重的损伤发生在较长时间没有日光的清晨。为了解决光暴露可以减轻缺血性心肌损伤的可能性，我们用强光对不同时期的小鼠进行了预处理。令人惊讶的是，我们观察到光治疗后心肌梗死面积和肌钙蛋白I释放的时间依赖性减少。对光诱导昼夜节律蛋白的研究发现，在强光照射下，心脏周期2(PER2)蛋白水平有很强的诱导作用。原理验证研究表明，光介导的心脏保护或PER2诱导分别在缺乏PER2蛋白的小鼠和没有感光能力的小鼠中被取消。基于这些发现， 我们假设，强光疗法通过稳定心脏PER2来提供强大的心脏保护，从而导致对缺血的心脏保护。为了解决这一假设，我们设计了三个具体的目标：1.确定光诱导的PER2稳定和心脏保护的剂量、时间和组织特异性来源；2.研究光治疗如何提供缺血和再灌注心脏保护的分子机制；3.阐明强光治疗对人类PER2蛋白稳定的影响。我们研究的长期目标是将强光疗法引入医院，以预防或治疗外科患者的心肌损伤，心肌损伤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在接近资助期结束时启动一项关于手术患者术前强光疗法的临床研究。

 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.