Mechanisms of Intrinsic Cardioprotection in Marmota momax

描述（由申请人提供）：哺乳动物冬眠是一种独特的冬季生存策略，以应对有限的食物供应和恶劣的气候。冬眠动物的心脏对室性心律失常/颤动表现出显著的耐受性和抵抗力，这在体温较低的非冬眠动物中观察到。冬眠哺乳动物可能是研究心肌缺血性疾病新机制的一种具有独特天然心脏保护作用的模型。我们观察到，冬眠的哺乳动物，如土拨鼠（旱獭monax）表现出从夏季到冬季的表型变化。他们表现出强大的心肌保护作用，在冬季对缺血/再灌注（I/R）损伤相比，土拨鼠在夏季，类似于缺血预处理阐明。事实上，冬眠的动物是通过唤起它们内在的心脏保护机制来为冬天做准备的。我们的初步研究结果还表明，cAMP反应元件结合蛋白（CREB），核转录因子，调节基因的表达对细胞存活和凋亡的重要性，是显着激活土拨鼠心脏在冬季和冬眠期间甚至更高。我们假设CREB的激活是一种潜在的新型分子，介导了冬季土拨鼠心脏的心脏保护作用。本提案的目的是（1）研究CREB在介导心脏保护中的重要性，并确定与CREB相关的其他关键信号分子，这些分子在心肌缺血情况下保护心脏免受凋亡和坏死;（2）研究介导传统IPC的机制是否也参与了在冬季土拨鼠心脏中观察到的心脏保护。长期目标是揭示冬眠哺乳动物对心脏应激的天然抵抗力所涉及的细胞和分子机制，并揭示心脏保护的主“开关”。对医疗保健的意义是明确的：了解冬眠动物的心脏适应机制可能会提出新的策略，以保护非冬眠动物的心肌，特别是人类，免受低温应激和心肌缺血引起的心脏功能障碍。项目叙述：对医疗保健的意义是明确的：了解冬眠动物的心脏适应机制可以提出保护非冬眠动物，特别是人类，由低温应激和心肌缺血引起的心脏功能障碍。

DESCRIPTION (provided by applicant): Mammalian hibernation is a unique strategy for winter survival in response to limited food supply and harsh climate. The hearts of hibernators exhibit remarkable tolerance and resistance to the ventricular arrhythmias/fibrillation that is observed in non-hibernators at lower body temperature. Hibernating mammals may be a model with unique natural cardioprotection to investigate novel mechanisms involved in myocardial ischemic disease. We observed that hibernating mammals such as woodchucks (Marmota monax) demonstrate a changed phenotype from summer to winter. They exhibit powerful myocardial protection in the winter against ischemia/reperfusion (I/R) injury compared to woodchucks in summer, similar to that elucidated by ischemic preconditioning. In fact, hibernating animals are "prepared" for winter by evoking their intrinsic cardioprotective mechanisms. Our preliminary results also demonstrate that the cAMP response element binding protein (CREB), a nuclear transcription factor, which regulates the expression of genes important for cell survival and apoptosis, is significantly activated in the woodchuck hearts in winter and even higher during hibernation. We hypothesize that the activation of CREB is a potentially novel molecule mediating this cardioprotection in the hearts of woodchucks in winter. The goal of this proposal is to (1) investigate the importance of CREB in mediating cardioprotection and to identify other key signaling molecules linked to CREB which protect the heart against apoptosis and necrosis following a myocardial ischemic instance; (2) examine whether mechanisms mediating traditional IPC are also involved in the cardioprotection observed in the woodchuck heart in the winter. The long term goal is to reveal the cellular and molecular mechanisms involved in natural resistance to cardiac stresses in hibernating mammals and to uncover the master "switch" for cardioprotection. The implications for health care are clear: understanding the cardiac adaptive mechanisms in hibernators may suggest new strategies to protect myocardium of non-hibernating animals, especially humans, from cardiac dysfunction induced by hypothermic stresses and myocardial ischemia.PROJECT NARRATIVE: The implications for health care are clear: understanding the cardiac adaptive mechanisms in hibernators may suggest new strategies to protect myocardium of non-hibernating animals, especially humans, from cardiac dysfunction induced by hypothermic stresses and myocardial ischemia.