Volatile anesthetics, calcium homeostasis and apoptosis

挥发性麻醉剂、钙稳态和细胞凋亡

• 批准号: 7057847
• 负责人: HUAFENG WEI
• 金额: $ 12.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057847
• 关键词: BCL2 gene /protein; Bax gene /protein; PC12 cells; age difference; anesthesia complication; apoptosis; calcium metabolism; cognition disorders; disease /disorder model; drug adverse effect; drug screening /evaluation; endoplasmic reticulum; ethers; homeostasis; immunocytochemistry; isoflurane; laboratory rat; learning disorders; molecular /cellular imaging; neural degeneration; neurotoxicology; sarcoplasmic reticulum; terminal nick end labeling; tissue /cell culture; western blottings; BCL2 gene /protein; Bax gene /protein; PC12 cells; age difference; anesthesia complication; apoptosis; calcium metabolism; cognition disorders; disease /disorder model; drug adverse effect; drug screening /evaluation; endoplasmic reticulum; ethers; homeostasis; immunocytochemistry; isoflurane; laboratory rat; learning disorders; molecular /cellular imaging; neural degeneration; neurotoxicology; sarcoplasmic reticulum; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): As an anesthesiologist, the applicant is firmly committed to advancing academic anesthesiology through basic research. His ultimate career goal is to improve peri-operative patient care, and his immediate career goal is to create more effective and safer general anesthetics. As an assistant professor in the tenure track, Dr. Wei will receive excellent training at the University of Pennsylvania. This proposal will complete his training and provide the initial transition to becoming an independent physician-scientist. Volatile genearal anesthetics are the most common agents used for maintenance of general anesthesia, but the increasing awareness of their long lasting effects on cognition and learning suggests enhanced neurodegeneration. The overall goal of this research project is to understand whether disruption of calcium homeostasis by volatile anesthetics leads to apoptosis. The immediate goal of the study is to investigate if isoflurane and sevoflurane interact with calcium homeostasis in the endoplasmic reticulum (ER) differently, thus contributing to neuronal apoptosis in different ways. The central hypothesis is that isoflurane, but not sevoflurane, induces neuronal apoptosis via depletion of calcium in the ER. We will test several sub hypotheses via the following specific aims: (1). Aim 1 will test that isoflurane, but not sevoflurane, induces apoptosis in both normal neurons and in a cell model of Alzheimer's disease because of its existing disruption of ER calcium. (2). Aim 2 will test the hypothesis that Isoflurane depletes, but sevoflurane maintains or increases, ER calcium contents. (3). Aim 3 will investigate if isoflurane and sevoflurane change the apoptosis-related Bcl-2 family proteins differently in cells. (4). Aim 4 will test the hypothesis that Isoflurane, but not sevoflurane, decreases the Bcl-2/Bax ratio, causing neuronal degeneration at different ages, resulting in learning deficits and/or cognitive dysfunction in the rat. We will examine neuronal apoptosis by histopathology, and learning and cognition change in animals after treatment of isoflurane or sevoflurane.

描述（由申请人提供）：作为麻醉师，申请人坚定地致力于通过基础研究来推进学术麻醉学。他的最终职业目标是改善围手术期的患者护理，他的直接职业目标是创造更有效，更安全的一般麻醉剂。 WEI博士作为任期的助理教授，将在宾夕法尼亚大学接受出色的培训。该建议将完成他的培训，并提供成为独立医师科学家的最初过渡。 挥发性的元人麻醉是用于维持全身麻醉的最常见药物，但是对它们对认知和学习的持久影响的认识越来越多，这表明神经变性的变化增强了。该研究项目的总体目标是了解挥发性麻醉药对钙稳态的破坏是否导致凋亡。该研究的直接目的是研究异氟烷和七氟醚与内质网（ER）中钙稳态相互作用是否有所不同，从而以不同的方式导致神经元细胞凋亡。中心假设是异氟烷，但不是七氟醚，可通过ER中的钙耗竭诱导神经元细胞凋亡。我们将通过以下特定目的测试几个子假设：（1）。 AIM 1将测试异氟烷，但不能测试七氟醚，诱导正常神经元和阿尔茨海默氏病细胞模型的凋亡，因为其现有的ER钙破坏了。 （2）。 AIM 2将检验异氟烷耗竭的假设，但Sevoflurane保持或增加钙含量。 （3）。 AIM 3将研究异氟烷和七氟醚在细胞中对与凋亡相关的Bcl-2家族蛋白的改变是否改变。 （4）。 AIM 4将检验异氟烷（而不是七氟）的假设降低了Bcl-2/Bax比率，从而导致不同年龄的神经元变性，从而导致大鼠学习缺陷和/或认知功能障碍。我们将通过组织病理学检查神经元凋亡，以及在治疗异氟烷或七氟醚后动物的学习和认知变化。