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The Effect of Isoflurane on Axonal Endoplasmic Reticulum Ca2+ Dynamics in Hippocampal Neurons

异氟醚对海马神经元轴突内质网 Ca2+ 动力学的影响

基本信息

批准号：
10163214
负责人：
Vanessa Osman
金额：
$ 4.6万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163214
关键词：
Address Affect Aftercare Agonist Anesthetics Axon Biosensor Ca(2+)-Transporting ATPase Clinical Complication Dantrolene Data Development Disease Drug usage Endoplasmic Reticulum Exocytosis Exposure to General anesthetic drugs Goals Hippocampus (Brain)Hyperthermia ITPR1 gene Isoflurane Link Malignant hyperpyrexia due to anesthesia Measures Mediating Mediator of activation protein Medicine Mental Depression Mentorship Modeling Modern Medicine Molecular Mechanisms of Action Mus Muscle Rigidity Mutation Neurons Pathway interactions Patient risk Patient-Focused Outcomes Patients Pharmacogenetics Pharmacology Predisposition Prevention Proteins Pump Rattus Regulation Role RyR1 Ryanodine Receptors Sarcoplasmic Reticulum Site Skeletal Muscle Symptoms Synapses Synaptic Transmission Synaptic Vesicles Tachycardia Testing clinically relevant experimental study hyperthermia treatment mouse model novel presynaptic presynaptic neurons receptor sensor tripolyphosphate

项目摘要

Project Summary/Abstract Volatile anesthetics are essential to modern medicine, but despite their widespread clinical use, their precise cellular and molecular mechanisms of action remain unclear. Volatile anesthetics, such as isoflurane, depress synaptic transmission with both pre- and post-synaptic effects including inhibition of activity-dependent Ca2+ influx into the presynaptic nerve terminal. However, the principal presynaptic sites of action upstream of Ca2+ entry are unknown. Axonal endoplasmic reticulum (ER) Ca2+ controls presynaptic Ca2+ through ER Ca2+ sensing proteins, and decreased ER Ca2+ has been linked to a reduction in presynaptic Ca2+ influx through these proteins. ER Ca2+ efflux and influx mechanisms are essential for Ca2+ regulation and provide possible targets for anesthetic action. For example, in skeletal muscle, mutations in sarcoplasmic reticulum (SR) Ca2+ efflux receptors: ryanodine receptors (RyR) result in patient with episodes of malignant hyperthermia (MH) after treatment with volatile anesthetics. MH is a potentially fatal pharmacogenetic disorder characterized by hyperthermia, tachycardia, muscle rigidity, and hypermetabolism [1]. However, MH's effect on neurons is unknown. As my preliminary data show, isoflurane decreases activity-dependent ER Ca2+ surges. Isoflurane inhibits presynaptic Ca2+ entry and synaptic vesicle (SV) exocytosis, which I hypothesize involves effects on ER Ca2+ efflux dynamics through ryanodine receptors (RyR). I will address this hypothesis through the following specific aims: 1) Determine the effects of isoflurane on ER Ca2+ efflux and influx pathways; 2) Determine the effect of isoflurane on ER Ca2+ in neurons from an MH model mouse. Primary cultures of rat hippocampal neurons will be used to test isoflurane-induced changes in ER Ca2+ concentration using fluorescent biosensors and pharmacological modulators of ER Ca2+ regulators. Under the mentorship of Dr. Hugh C. Hemmings Jr. at Weill Cornell Medicine, I plan to further our understanding of isoflurane's neuronal mechanisms of action. Successful completion of these aims will reveal novel presynaptic mechanisms and aid in the development of more-selective anesthetics decreasing patient risk as well as facilitate the improvement of MH patient outcomes.

项目总结/摘要挥发性麻醉剂对现代医学是必不可少的，但是尽管它们广泛地用于临床，确切的细胞和分子作用机制仍不清楚。挥发性麻醉剂，如异氟烷抑制突触传递，具有突触前和突触后效应，包括抑制活动依赖性Ca 2+内流进入突触前神经末梢。然而，主要的突触前位点 Ca 2+进入上游的作用是未知的。轴突内质网（ER）Ca 2+对照突触前Ca 2+通过ER Ca 2+传感蛋白，ER Ca 2+减少与突触前Ca 2+减少有关。突触前Ca 2+通过这些蛋白质内流。ER Ca 2+流出和内流机制对于 Ca ~（2+）的调节，为麻醉作用提供可能的靶点。例如，在骨骼肌中，肌浆网（SR）钙外排受体：兰尼碱受体（RyR）突变导致患者用挥发性麻醉剂治疗后恶性高热（MH）发作。MH是一种潜在的以高热、心动过速、肌肉强直和高代谢[1]。然而，MH对神经元的影响尚不清楚。我的初步数据显示，异氟烷降低活性依赖性ER Ca 2+峰。异氟烷抑制突触前Ca 2+内流和突触囊泡（SV）胞吐，一种假说涉及通过兰尼碱受体（RyR）对ER Ca 2+流出动力学的影响。我会通过以下具体目标来解决这一假设：1）确定异氟烷对ER的影响 Ca 2+流出和内流途径; 2）确定异氟醚对MH神经元中ER Ca 2+的影响模型小鼠。大鼠海马神经元的原代培养物将用于测试异氟醚诱导的使用荧光生物传感器和ER的药理学调节剂的ER Ca 2+浓度变化 Ca 2+调节剂。在Hugh C博士的指导下，小亨明斯在威尔康奈尔医学院，我计划进一步了解异氟烷的神经元作用机制。成功完成这些 aims将揭示新的突触前机制，并有助于开发更具选择性的麻醉剂降低患者风险以及促进MH患者结局的改善。