2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646254摘要：突發性心跳停止經初步心肺復甦急救後，常會由於缺血再灌流而引發之急性心肌功能失常而導致死亡，心肌能量的供需失調為其中重要因素。低溫治療已被確認為改善心跳停止復甦後急救之心臟功能失常及長期預後最有效的方式，然而其機轉仍未確立。代謝體研究(metabolomics)是透過對體內代謝產物的全面性分析，來瞭解生物體內不同疾病狀況下整體代謝的變化及疾病之機轉，對於能量相關代謝產物的分析有獨到之處。而心肌在受到缺血再灌流傷害時，AMPK (AMP-Activated Protein Kinase)的活化對能量維持有重要的作用，低溫治療在心肌細胞的研究上也發現可活化AMPK 此能量路徑。本研究的目的即是應用代謝體的研究模式探討心跳停止復甦急救後心肌功能失常與能量失衡的關係，及低溫治療對能量保存的效果及機轉。本研究計畫中，第一年將先建立心跳停止復甦急救動物模式，確定低溫治療對心臟功能的保護效果，並以targeted metabolomics 及metabolomic profiling 的方式，比較不同時間點及治療模式下，代謝產物的變化。第二年則是探討在低溫治療下，心肌能量調控相關之酵素、訊息傳遞路徑、粒線體功能的變化，並與代謝體結果比對，以釐清心肌能量失調及低溫保護作用的機轉及可能應用。第三年則是以先前建立的模式，調控AMPK 此一能量樞紐路徑，探討低溫治療的效果是否經由此一路徑，以及合併低溫治療及AMPK 活化是否可發揮加乘的保護效果，來釐清此能量調控對心肌保護的重要性，並做為發展潛在新治療的基礎。<br> Abstract: Myocardial dysfunction is a major cause of early mortality after sudden cardiac arrestand cardiopulmonary resuscitation. The global ischemia reperfusion injury causes the failureof energy utilization and balance which leads to post-cardiac arrest myocardial dysfunction.Therapeutic hypothermia is the most effective treatment for the post-cardiac arrestmyocardial dysfunction and can improve the long-term survival. However, the mechanism ofits protective effects remained unclear. Metabolomics study is a way of measuring andanalyzing the small molecular metabolites of whole body in different physiological orpathological conditions. It is help in comparing the different metabolic status in differentclinical situations and disease statuses. The investigation of energy and metabolic changes isfeasible by using the metabolomic approach. Activation of AMPK (AMP-Activated ProteinKinase) is critical important in maintaining the energy balance when myocardial ischemiareperfusion injury happens. It is found that AMPK is activated after hypothermia treatmentagainst ischemia reperfusion injury in cardiomyocyte study. The aim of the project is toinvestigate the myocardial energy failure in post-cardiac arrest myocardial dysfunction andthe energy preservation by hypothermia treatment by using the metabolomic approach.The study project includes 3 years planning for experiments. In the first year, we willestablish the cardiac arrest a cardiopulmonary resuscitation model and measure themyocardial dysfunction in post-resuscitation period. The hypothermia treatment will beapplied and cardio-protection effects will be confirmed in the model. The difference ofmetabolites will be compared between different time points and treatment modalities byusing the metabolomic approaches, including target metabolomics and metabolomicprofiling. In the second year, we will investigate the changes of energy-related kineticenzymes, signaling pathways, mitochondria function and integrity after cardiac arrest with orwithout hypothermia treatment in post-resuscitation myocardium. These changes will becorrelated with the metabolites changes in metabolomic studies to elucidate the mechanismof hypothermia treatment and potential applications. In the third year, we will regulate theenergy pathway AMPK in animal model established in the first year. We will evaluate thecardio-protective effects of activating the AMPK pathway in post-resuscitation myocardialdysfunction. Then we will inhibit the AMPK pathway under hypothermia treatment to seethe potential critical role of AMPK in the hypothermia-induced cardio-protection. Finally,we will activate the AMPK and apply hypothermia treatment concurrently to check whetheradditive cardio-protective effect appears. By evaluating the interaction of AMPK andhypothermia treatment, the mechanism of hypothermia treatment can be clarified. Theresults can also be the basis of developing new therapeutic modality.