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学术麻醉学。他的最终职业目标是改善围手术期患者护理，他的直接职业目标是创造更有效，更安全的全身麻醉药。作为终身教职的助理教授，魏博士将在宾夕法尼亚大学接受出色的培训。这项建议将完成他的训练，并提供初步过渡，成为一个独立的医生，科学家。 挥发性全身麻醉药是维持全身麻醉最常用的药物，但越来越多的人意识到它们对认知和学习的长期影响表明神经退行性变增强。本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研究异氟烷和七氟烷是否以不同方式与内质网（ER）中的钙稳态相互作用，从而以不同方式促进神经元凋亡。中心假设是异氟烷（而非七氟烷）通过消耗ER中的钙诱导神经元凋亡。我们将通过以下具体目标来检验几个子假设：（1）。目的1将测试异氟烷，而不是七氟烷，诱导正常神经元和阿尔茨海默病的细胞模型中的细胞凋亡，因为其现有的ER钙的破坏。（二）、目的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。（三）、目的3研究异氟醚和七氟醚对细胞凋亡相关Bcl-2家族蛋白的影响是否存在差异。（四）、目的4将检验异氟烷（而非七氟烷）降低Bcl-2/Bax比值，导致不同年龄大鼠神经元变性，导致大鼠学习缺陷和/或认知功能障碍的假设。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。