Volatile anesthetic alteration of neural precursor cell cycle and fate decisions

描述（由申请人提供）：PI的长期目标是发展成为一名学术麻醉师，拥有独立的研究计划，专注于麻醉和神经发育。该提案概述了一个职业发展计划，包括神经发育和干细胞生物学的教学和实验室指导。在此过程中，PI将获得未来在该领域竞争独立资金所需的几项新技能。该研究和教学项目将在加州大学旧金山分校麻醉和围手术期护理部门进行，该部门是该领域的顶级部门之一。所有的全身麻醉剂都部分作用于GABA或NMDA受体，最近的研究已经确定了GABA和NMDA介导的信号在神经祖细胞（npc）的生长和分化中的重要作用。因此，挥发性麻醉剂作用于这些已知和其他未知的位点可能会改变npc的增殖、分化和存活，从而对中枢神经系统功能产生长期影响。海马齿状回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、体内和啮齿类动物中都能降低npc的增殖，我们观察到异氟醚暴露后3周到8个月的海马认知缺陷。我们认为麻醉后长期海马认知缺陷是麻醉诱导海马npc变化的结果。我们将检验麻醉药诱导npc细胞周期退出和过早分化的假设。目的1将集中于体外麻醉作用于npc的机制。目的2将研究麻醉暴露后海马齿状回细胞结构的变化。综上所述，这些目标将开始定义麻醉剂对海马发育的影响。

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. )