Volatile anesthetic alteration of neural precursor cell cycle and fate decisions

神经前体细胞周期和命运决定的挥发性麻醉改变

基本信息

批准号：
8212430
负责人：
Jeffrey W Sall
金额：
$ 11.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212430
关键词：
1-Phosphatidylinositol 3-Kinase Adult Anesthesia procedures Anesthetics Animals Architecture Area Bicuculline Biological Assay Brain Bromodeoxyuridine Calcium California Caspase Cell Culture Techniques Cell Cycle Cell Death Cell Differentiation process Cell division Cell surface Cells Chelating Agents Child Cognition Cognitive Cognitive deficits Communities Data Development Development Plans Differentiation and Growth Enzymes Event Fluorescence Funding Fura-2 Future GABA Receptor General Anesthesia General anesthetic drugs Goals Growth Hippocampus (Brain)Hour Impaired cognition In Vitro Instruction Isoflurane Knowledge Laboratories Lead Learning Learning Disabilities Link Long-Term Effects Mediating Memory Mentors Mitogen-Activated Protein Kinases Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate Neonatal Neurons Newborn Animals Pathway interactions Perioperative Care Phosphorylation Play Principal Investigator Process Publications Qualifying Rattus Receptor Activation Reporting Research Retrospective Studies Rodent Role San Francisco Signal Pathway Signal Transduction Site Source Specificity Stem cells Structure Testing United States National Institutes of Health Universities Western Blotting base brain cell brain tissue career development clinical practice cognitive function dentate gyrus gamma-Aminobutyric Acid genetic manipulation gliogenesis immunocytochemistry in vivo migration nerve stem cell neural precursor cell neurodevelopment neurogenesis premature progenitor programs public health relevance receptor relating to nervous system research study sevoflurane skills stem stem cell biology

项目摘要

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. )

描述（由申请人提供）：PI的长期目标是发展为学术麻醉师，其独立研究计划的重点是麻醉和神经发育。该提案概述了一项职业发展计划，其中包括基于教学和实验室的神经发育和干细胞生物学指导。在其课程中，PI将获得几种必要的新技能，以竞争将来在这一领域的独立资金。该研究和教学计划将在加利福尼亚大学，旧金山分校的麻醉和围手术期护理系，该领域是该领域的顶级部门之一。所有通用麻醉药都在GABA或NMDA受体中作用，最近的研究确定了GABA和NMDA介导的信号在神经祖细胞的生长和分化（NPC）中的重要作用。因此，作用于这些已知和其他未知部位的挥发性麻醉药可能会改变NPC的增殖，分化和存活，对长期对CNS功能的影响产生影响。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。我们的初步数据表明，异氟烷在体外和体内和啮齿动物中降低了NPC的增殖，并且在异氟烷暴露后3周到8个月，我们观察到海马认知不足。我们建议麻醉后长期基于海马的认知缺陷是麻醉诱导海马NPC变化的结果。我们将检验以下假设，即麻醉药会诱导NPC中的细胞周期出口和过早分化。 AIM 1将专注于在体外对NPC的麻醉作用机制。 AIM 2将调查体内麻醉剂暴露后海马齿状回的细胞体系结构的变化。这些目标将共同开始定义麻醉剂对海马发育的影响。公共卫生相关性：新生动物全身麻醉后的长期认知缺陷的近期鉴定引起了人们对临床实践的重大关注。该提议试图了解麻醉剂如何改变海马中的神经发育和神经前体。）