Mechanisms of Intrinsic Cardioprotection in Marmota momax

旱獭 momax 的内在心脏保护机制

• 批准号: 7842248
• 负责人: Lin Yan
• 金额: $ 20.96万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842248
• 关键词: Abbreviations; Affinity Chromatography; Analysis of Variance; Animals; Apoptosis; Area; Biological Preservation; Body Temperature; Cardiac; Cell Survival; Chloride Ion; Chlorides; Climate; Coronary artery; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Disease; Dominant-Negative Mutation; Drops; EFRAC; Exhibits; Food; Food Supply; Functional disorder; Gene Expression; Genomics; Glossary; Goals; Healthcare; Heart; Hibernation; Human; Infarction; Ischemia; Ischemic Preconditioning; Isoelectric Focusing; Lasers; Left; Left Ventricular Function; Link; MALDI-TOF Mass Spectrometry; Mammals; Marmota; Mediating; Metabolic; Metals; Microarray Analysis; Modeling; Molecular; Myocardial; Myocardial Ischemia; Myocardium; Natural Resistance; Necrosis; Nitric Oxide; Nuclear; Phenotype; Physiological; Poly(ADP-ribose) Polymerases; Proteins; Proteomics; Reperfusion Injury; Reperfusion Therapy; Resistance; Risk; Signal Transduction; Signaling Molecule; Stress; Temperature; Tetrazolium; Time; Two-Dimensional Gel Electrophoresis; Ventricular; Ventricular Arrhythmia; Woodchuck; artery occlusion; novel; preconditioning; pressure; protein activation; response; transcription factor

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.

描述（由申请人提供）：哺乳动物冬眠是应对有限的食物供应和恶劣气候的冬季生存的独特策略。冬眠者的心脏对室性心律失常/颤动表现出显着的耐受性和抵抗力，这在非冬眠者在较低体温下观察到。冬眠哺乳动物可能是具有独特自然心脏保护作用的模型，可用于研究心肌缺血性疾病的新机制。我们观察到冬眠的哺乳动物，如土拨鼠（Marmota monax），从夏季到冬季表现出不同的表型。与夏季的土拨鼠相比，它们在冬季表现出强大的心肌保护作用，以防止缺血/再灌注（I/R）损伤，这与缺血预处理所阐明的相似。事实上，冬眠动物通过激发其内在的心脏保护机制来“准备”过冬。我们的初步结果还表明，cAMP 反应元件结合蛋白（CREB）是一种核转录因子，调节对细胞生存和凋亡重要的基因的表达，在冬季土拨鼠心脏中显着激活，在冬眠期间甚至更高。我们假设 CREB ​​的激活是一种潜在的新分子，在冬季土拨鼠的心脏中介导这种心脏保护作用。该提案的目标是（1）研究 CREB ​​在介导心脏保护方面的重要性，并确定与 CREB ​​相关的其他关键信号分子，这些信号分子可以在心肌缺血情况下保护心脏免受细胞凋亡和坏死； (2) 检查介导传统 IPC 的机制是否也参与在冬季土拨鼠心脏中观察到的心脏保护作用。长期目标是揭示冬眠哺乳动物对心脏应激的自然抵抗力的细胞和分子机制，并揭示心脏保护的主要“开关”。对医疗保健的影响是显而易见的：了解冬眠者的心脏适应性机制可能会提出新的策略，以保护非冬眠动物（尤其是人类）的心肌免受低温应激和心肌缺血引起的心脏功能障碍的影响。 项目叙述：对医疗保健的影响很明显：了解冬眠者的心脏适应性机制可能会提出新的策略，以保护非冬眠动物（尤其是人类）的心肌免受低温应激和心肌病引起的心脏功能障碍的影响。缺血。