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

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）：作为一名麻醉师，申请人坚定地致力于通过基础研究推进麻醉学学术发展。他的最终职业目标是改善围手术期患者护理，而他的近期职业目标是创造更有效、更安全的全身麻醉剂。作为终身教授助理教授，魏博士将在宾夕法尼亚大学接受良好的培训。该提案将完成他的培训，并为成为一名独立的医师科学家提供初步过渡。 挥发性全身麻醉剂是维持全身麻醉最常用的药物，但人们越来越认识到它们对认知和学习的长期影响表明神经退行性加剧。该研究项目的总体目标是了解挥发性麻醉剂对钙稳态的破坏是否会导致细胞凋亡。该研究的直接目标是调查异氟烷和七氟烷是否与内质网（ER）中的钙稳态相互作用不同，从而以不同的方式促进神经元凋亡。中心假设是异氟烷（而不是七氟烷）通过消耗内质网中的钙来诱导神经元凋亡。我们将通过以下具体目标测试几个子假设：（1）。目标 1 将测试异氟烷（而非七氟烷）会诱导正常神经元和阿尔茨海默病细胞模型的细胞凋亡，因为它会破坏内质网钙。 （2）。目标 2 将检验异氟烷消耗但七氟烷维持或增加 ER 钙含量的假设。 （3）。目标 3 将研究异氟烷和七氟烷是否以不同方式改变细胞中与凋亡相关的 Bcl-2 家族蛋白。 （4）。目标 4 将检验以下假设：异氟烷（而非七氟烷）会降低 Bcl-2/Bax 比率，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，以及异氟烷或七氟烷治疗后动物的学习和认知变化。