Volatile anesthetics, calcium homeostasis and apoptosis

描述(申请人提供)：作为一名麻醉师，应聘者坚定地致力于通过基础研究促进麻醉学学术的发展。他的最终职业目标是改善围手术期病人的护理，而他近期的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。这项提议将完成他的培训，并为成为一名独立的内科科学家提供初步过渡。 挥发性全麻药是维持全身麻醉最常用的药物，但人们对其对认知和学习的长期影响的认识日益增强，表明神经退行性变加剧。本研究项目的总体目标是了解挥发性麻醉药破坏钙稳态是否会导致细胞凋亡。本研究的直接目的是研究异氟烷和七氟烷是否以不同的方式与内质网(ER)中的钙稳态相互作用，从而以不同的方式促进神经元凋亡。中心假设是异氟醚，而不是七氟醚，通过耗尽内质网中的钙而诱导神经元凋亡。我们将通过以下具体目标检验几个子假设：(1)。目的1将测试异氟烷，但不是七氟烷，诱导正常神经元和阿尔茨海默病细胞模型的细胞凋亡，因为它存在内质网钙的干扰。(2)。目的2验证异氟醚消耗，但七氟醚维持或增加内质网钙含量的假说。(3)。目的3研究异氟醚和七氟醚对细胞中与细胞凋亡相关的Bcl2家族蛋白的影响是否不同。(4)。目的4将测试假设，即异氟醚，而不是七氟醚，降低了Bcl2/Bax比率，导致不同年龄的神经元变性，导致大鼠学习障碍和/或认知功能障碍。我们将通过组织病理学以及异氟醚或七氟醚治疗后动物学习和认知的变化来检测神经细胞的凋亡。

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.