Volatile anesthetic alteration of neural precursor cell cycle and fate decisions

描述(由申请者提供)：PI的长期目标是发展成为一名学术麻醉师，拥有专注于麻醉药和神经发育的独立研究计划。这份提案概述了一项职业发展计划，其中包括神经发育和干细胞生物学方面的教学和实验室指导。在其过程中，国际和平研究所将获得几项必要的新技能，以便在未来争取这一领域的独立资金。这项研究和教学计划将在加州大学旧金山分校的麻醉和围术期护理系进行，这是该领域的顶级系之一。所有的全身麻醉药都部分作用于GABA或NMDA受体，最近的研究发现GABA和NMDA介导的信号在神经前体细胞的生长和分化中起着重要作用。因此，作用于这些已知和其他未知部位的挥发性麻醉剂可能会改变NPC的增殖、分化和存活，并对中枢神经系统功能产生长期影响。海马齿状回中的神经发生对于某些类型的学习和记忆是必要的。我们的初步数据显示，异氟醚在体外、体内和啮齿动物体内都能减少NPC的增殖，我们观察到异氟醚暴露3周至8个月后，海马区认知障碍。我们认为麻醉后长期的基于海马区的认知障碍是麻醉诱导的海马区神经前体细胞改变的结果。我们将验证麻醉剂诱导鼻咽癌细胞周期退出和提前分化的假设。目的1重点研究麻醉剂对体外培养的鼻咽癌细胞的作用机制。目的2研究麻醉后在体海马齿状回细胞构筑的变化。这些目标加在一起将开始定义麻醉剂对海马体发育的影响。 公共卫生相关性：最近在新生动物全身麻醉后发现的长期认知缺陷已经引起了临床实践的极大关注。这项提议试图了解麻醉剂如何改变海马体中的神经发育和神经前体。)

DESCRIPTION (provided by applicant): The long-term goal of the PI is develop into an academic anesthesiologist with an independent research program focused on anesthetics and neural development. This proposal outlines a career development plan that includes didactic and laboratory based instruction in neural development and stem cell biology. During its course the PI will obtain several new skills necessary to compete for independent funding in this field in the future. The research and didactic program will be carried out at the University of California, San Francisco in the department of Anesthesia and Perioperative Care, one of the top departments in this field. All general anesthetics act in part at GABA or NMDA receptors and recent research has identified an important role for GABA and NMDA mediated signals in growth and differentiation of neural progenitor cells (NPCs). Therefore, volatile anesthetics acting at these known and other unknown sites may alter proliferation, differentiation and survival of NPCs with implications for long-term effects on CNS function. Neurogenesis in the hippocampal dentate gyrus is necessary for certain types of learning and memory. Our preliminary data show isoflurane decreases proliferation of NPCs both in vitro and in vivo and in rodents and we have observed a hippocampal cognitive deficit 3 weeks to 8 months after isoflurane exposure. We propose that long-term hippocampal-based cognitive deficits following anesthesia are a consequence of anesthetic induced changes in hippocampal NPCs. We will test the hypothesis that anesthetics induce cell cycle exit and premature differentiation in NPCs. Aim 1 will focus on mechanisms of anesthetic action on NPCs in vitro. Aim 2 will investigate changes in the cyto-architecture of the hippocampal dentate gyrus after anesthetic exposure in vivo. Together these aims will begin to define the effect of anesthetics on hippocampal development. PUBLIC HEALTH RELEVANCE: Recent identification of long-term cognitive deficits following general anesthesia in neonatal animals has caused significant concern for clinical practice. This proposal seeks to understand how anesthetics alter neural development and neural precursors in the hippocampus. )