Role of Autophagy in Post-Resuscitation Myocardial Dysfunction and Its Therapeutic Implications

View Statistics Email Alert RSS Feed

Information

Details

Project title/計畫英文名

Project Number/計畫編號

MOST105-2314-B002-125-MY3

Translated Name/計畫中文名

Autophagy於心跳停止復甦急救後心肌失常之角色及治療潛力

Project Principal Investigator/計畫主持人

CHIEN-HUA HUANG

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

黃溫雅,陳惠文,陳文鍾

Website

link

Start date/計畫起

01-08-2016

Expected Completion/計畫迄

31-07-2018

摘要：心肺復甦急救的發展改善了心跳停止病患恢復自發性循環的機會，然而缺血再灌流的傷害、氧化壓力的產生、發炎反應的進行及多重器官急性失能之合併機轉，使復甦後心臟功能持續惡化並導致死亡，因此改善心臟功能為首要任務。心肌受損過程中，細胞內的蛋白、醣類、脂質及核酸等都受到破壞，粒線體及相關胞器也受到損傷，不只無法進行正常功能，甚至會引發進一步傷害而加速細胞凋亡及壞死的進行。近來發現autophagy 為細胞內清除代謝受損的物質及粒線體等胞器之重要過程，因缺血再灌流受損的心肌，可藉由強化autophagy 的過程，來改善心肌的功能及存活預後，可能與重新利用細胞內受損的代謝物，減少氧化壓力造成粒線體傷害及細胞凋亡有關，其機轉仍有許多待釐清之處，然而調控autophagy 此治療模式有相當的潛力，在針對復甦後心臟功能失常之效果仍未明。本計畫第一年將應用心跳停止復甦急救動物模式，檢視autophagy 在於復甦後心臟功能失常的角色，並探討與autophagy 相關氧化壓力、細胞凋亡等面向之機轉。之後進一步調控autophagy 之活化或抑制，來探討對心臟失調及存活預後的效果，並與各種機轉進行關聯比較，找出潛在可能之最佳治療模式，此部分將在第二年完成。低溫治療現已是治療準則所建議的標準治療，在低溫之下，autophagy本身或調控的效果是否會因此而影響，或因機轉之互補而增加保護效果則未知。第三年則是在調控autophagy 治療模式發展出來之後，釐清其在現行低溫治療下之變化或調整方式，以作為臨床應用的基礎。
Abstract: Recent development of cardiopulmonary resuscitation medicine improves the chance of returnspontaneous circulation in cardiac arrest. However, the ischemia reperfusion injuries, oxidative stress,progression of inflammatory reactions and acute multiple organ failure keep deteriorating thepost-resuscitation myocardial dysfunction and lead to mortality. Therefore, it is the key issue to improvecardiac dysfunction for achieving better outcomes. Cellular proteins, lipids, nucleic acid, mitochondria andother organelles are damaged after myocardial ischemia-reperfusion injuries. These damaged substances andorganelles not only loose normal functions, but precipitate and accelerate cellular apoptosis and necrosis.Autophagy is recently found as a way to re-cycle the intracellular damaged substance and organellesincluding mitochondria. Activation and strengthening the autophagy can reduce the myocardial damage andimprove outcome after ischemia-reperfusion injury through the mechanisms of re-utilization of intracellularsubstance and ameliorating the mitochondria damage. Although the mechanisms remain unclear, modulatingautophagy has potentials in treating diseases. The effects of modulating autophagy on post-resuscitationmyocardial dysfunction are still unclear.We plan to investigate the responses of autophagy on myocardial dysfunction and survival outcomes incardiac arrest and resuscitation animal model in the first year. The mechanisms related to the autophagyincluding oxidative stress and apoptosis will be studied to elucidate the critical pathways of improvingcardiac function and survival. We will modulate the autophagy and evaluate the possible protective effects ofactivation or inhibition autophagy to find the optimal treatment model for post-resuscitation myocardialdysfunction. Because of the multiple aspects of mechanisms, we will study and correlate the potentialmechanisms with the effects of modulating autophagy to develop the new treatment targets in the secondyear project. Hypothermia treatment has been a guideline-recommended standard treatment in post-cardiacarrest care. However, whether the effects of modulating autophagy are interfered or synergized byhypothermia treatment remains unclear. In the third year, we will investigate the influence of therapeutichypothermia on modulating autophagy model and the ways to adjusting the treatment for improving thetherapeutic effects under therapeutic hypothermia. The results are the bases for improving clinicalmanagements for cardiac arrest patients.

DSpace CRIS

Role of Autophagy in Post-Resuscitation Myocardial Dysfunction and Its Therapeutic Implications

Details

Description