APOPTOSIS AND OXIDANTS AFTER MURINE CARDIAC ARREST

小鼠心脏骤停后的细胞凋亡和氧化剂

• 批准号: 6931137
• 负责人: Lance B. Becker
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931137
• 关键词: BCL2 gene /protein; Bax gene /protein; CD95 molecule; antioxidants; apoptosis; cardiopulmonary resuscitation; cardiovascular injury; cysteine endopeptidases; cytoprotection; gene targeting; genetically modified animals; heart arrest; heart disorder chemotherapy; laboratory mouse; myocardial ischemia /hypoxia; nonhuman therapy evaluation; oxidative stress; oxidizing agents; protease inhibitor; reperfusion

EXCEED THE SPACE PROVIDED. Using a murine cardiac arrest model, we will define oxidant-mediated apoptosis in the post-resuscitation phase of irdiac arrest. Our proposal extends work by others and our own cellular studies that implicate oxidant-mediated apoptosis as a cause of significant cell and organ injury after reperfusion following ischemia. This post resuscitation injury may be particularly important following the global ischemia of cardiac arrest, after which almost 90% of patients go on to die hours to days later even after an initially "successful" immediate resuscitation. The Emergency Resuscitation Center at the University of Chicago has developed a translational murine model of cardiac arrest which reflects this post-resuscitation injury, demonstrates activation of cellular apoptotic markers and oxidant-mediated transcriptional changes 18 hours after cardiac arrest, and will allow use of genetically altered nimals to further define post-resuscitation processes. Specifically, we aim to use this new model to define the role of intrinsic and extrinsic apoptotic pathways in key organs during post-resuscitation injury and death following murine cardiac arrest. We will test the contribution of the intrinsic apoptotic pathway during cardiac arrest by treatment of mice with a caspase 9 inhibitor, and by using Bcl-2 and Bax knockout mice, which exhibit alterations in apoptotic function. We will test the contribution of the extrinsic apoptotic pathway by studying cardiac arrest in mice treated with a caspase 8 inhibitor, and by using Fas-deflcient and Fas ligand-deficient mice. We also aim to define the contribution of oxidants to the sequence of apoptosis. To do this, we will study cardiac arrest while treating mice with antioxidants and by using superoxide dismutase (SOD1) transgenic mice, both alterations known to be protective during ischemia. Outcomes in these studies will include multiple markers of apoptosis, oxidant generation, hemodynamics, neurologic function, cardiac function and survival to 7 days. The highlight of this translational model is its ability to provide insights into integrative physiology, test for similarities and differences between organs exposed to the same ischemic insult, and test for the remote effects that one organ may have on distant organs. Finally we will ask whether antiapoptotic and antioxidant therapies can improve survival and function after cardiac arrest, a leading cause of death in our society. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。 使用小鼠心脏骤停模型，我们将定义虹膜骤停复苏后阶段氧化剂介导的细胞凋亡。我们的建议扩展了其他人和我们自己的细胞研究的工作，这些研究表明氧化剂介导的细胞凋亡是缺血再灌注后严重细胞和器官损伤的原因。这种复苏后损伤可能在心脏骤停引起的全身缺血后尤为重要，之后几乎 90% 的患者即使在最初“成功”的立即复苏后几小时至几天后仍会死亡。 芝加哥大学紧急复苏中心开发了一种心脏骤停的转化小鼠模型，该模型反映了这种复苏后的损伤，展示了心脏骤停后 18 小时细胞凋亡标记物的激活和氧化剂介导的转录变化，并且将允许使用基因技术改变动物以进一步定义复苏后过程。具体来说，我们的目标是使用这种新模型来定义小鼠心脏骤停后复苏后损伤和死亡期间关键器官中内在和外在凋亡途径的作用。我们将通过用 caspase 9 抑制剂治疗小鼠，并使用 Bcl-2 和 Bax 敲除小鼠（这些小鼠表现出细胞凋亡功能的改变）来测试心脏骤停期间内在细胞凋亡途径的贡献。我们将通过研究用 caspase 8 抑制剂治疗的小鼠的心脏骤停以及使用 Fas 缺陷和 Fas 配体缺陷的小鼠来测试外源性细胞凋亡途径的贡献。我们还旨在确定氧化剂对细胞凋亡序列的贡献。为此，我们将在用抗氧化剂和超氧化物歧化酶 (SOD1) 转基因小鼠治疗小鼠时研究心脏骤停，这两种改变已知在缺血期间具有保护作用。这些研究的结果将包括细胞凋亡、氧化剂生成、血流动力学、神经功能、心脏功能和 7 天生存的多种标志物。 这种转化模型的亮点是它能够提供对综合生理学的见解，测试暴露于相同缺血性损伤的器官之间的相似性和差异，并测试一个器官可能对远处器官产生的远程影响。最后我们要问抗凋亡和抗氧化疗法是否可以改善心脏骤停（我们社会死亡的主要原因）后的生存和功能。表演网站==========================================部分结束====== =======================================