Intense Light Therapy for Perioperative Cardio-Protection

 描述（由申请人提供）：急性心肌梗死是手术患者围手术期短期和长期发病率和死亡率的最重要预测因素之一。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，如经皮冠状动脉介入联合抗凝和血小板抑制剂，可能不适合围手术期设置，由于手术部位出血的风险。因此，使心肌对缺血更具抵抗力并减轻心肌再灌注损伤的其他治疗方法是一个激烈的研究领域。人类流行病学研究表明，缺血性心肌组织损伤的易感性是一天中的时间依赖性的，更严重的损伤发生在较长时间没有日光后的清晨。为了解决光暴露可以起到减轻缺血性心肌损伤的作用的可能性，我们用强光对小鼠进行了不同时间的预处理。令人惊讶的是，我们观察到心肌梗死面积和肌钙蛋白I释放的光治疗后的时间依赖性减少。对光诱导的昼夜节律蛋白的搜索揭示了在强光暴露后心脏周期2（Per2）蛋白水平的稳健诱导。原理验证研究表明，光介导的心脏保护或Per2诱导在缺乏Per2蛋白的小鼠或没有感知光的能力的小鼠中分别被消除。根据这些发现， 我们假设强光疗法通过稳定心脏Per2提供了强有力的心脏保护，从而导致伴随的心脏保护免于缺血。为了解决这一假设，我们设计了三个具体目标：1。定义光诱导Per2稳定和心脏保护的剂量、时间和组织特异性来源，2.研究光疗法如何提供心肌缺血和再灌注保护的分子机制，3。阐明强光治疗对人类PER2蛋白稳定性的影响。我们研究的长期目标是将强光疗法引入医院，以预防或治疗手术患者的心肌损伤，这是术后发病率和死亡率的最常见原因。我们预计，我们的目标的成功完成将使我们能够在资助期的艾德开始对手术患者进行术前强光治疗的临床研究。

 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.