The role of caveolin-1 on anesthetic-mediated neurotoxicity

Caveolin-1 对麻醉介导的神经毒性的作用

• 批准号: 10393511
• 负责人: MATTHEW L PEARN
• 金额: $ 20.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393511
• 关键词: Actins; Anesthetics; Animals; Award; Axonal Transport; Binding; Biological Assay; Biology; Blood; Brain; Brain-Derived Neurotrophic Factor; Buffers; Cell membrane; Child; Clinical Data; Cognition; Cognitive deficits; Data; Development; Electrophysiology (science); Equilibrium; Exposure to; Foundations; Funding; Future; Goals; Grant; Growth Cones; Hippocampal Mossy Fibers; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Individual; Laboratories; Leadership; Learning; Manuscripts; Measures; Mediating; Membrane; Mentors; Molecular Target; Morphology; Neonatal; Nerve Degeneration; Neurons; Pharmacology; Play; Population; Predisposition; Propofol; Research; Research Personnel; Role; Scaffolding Protein; Scientific Advances and Accomplishments; Scientist; Secure; Signal Transduction; Stress Fibers; Synapses; Testing; Therapeutic Intervention; Time; Toxic effect; Uncertainty; United States National Institutes of Health; Viral Vector; Work; Writing; caveolin 1; clinically translatable; experimental study; human data; improved; in vivo; inhibitor; insight; neuron development; neuron loss; neuronal circuitry; neurotoxicity; neurotrophic factor; potential biomarker; predictive marker; prevent; public health relevance; skills; synaptogenesis; therapeutic biomarker; therapeutic target

Abstract Dr. Matthew Pearn has established himself as a promising researcher in the field of anesthetic-mediated neurotoxicity and axonal transport. He has secured and completed a two year FAER grant, investigating the role of RhoGTPase signaling, growth cone (GC) collapse, and axonal transport on anesthetic related neurotoxicity. This NIH K08 proposal extends his research, investigating the role of caveolin-1 (Cav1) on anesthetic-mediated neurotoxicity. The K08 Award will provide Dr. Pearn with the funding and protected time needed to accomplish the following goals: (1) to become an expert in the study of Cav1 biology, (2) to further advance his scientific writing and increase the volume of first author manuscripts, (3) to learn lab management and leadership skills, (4) to successfully acquire independent funding, and (5) to develop into a independent clinician-scientist. To accomplish these goals, Dr. Pearn has assembled a mentoring team comprised of Dr. Hemal Patel and Dr. Piyush Patel. Growth cone collapse and axonal transport is recognized as being critical for neuronal development and cognition. Both GC morphology and axonal transport are influenced by actin dynamics, which it turn are influenced by RhoGTPase signaling. Dr. Pearn has shown that neonatal neurons exposed to propofol (PPF) have increased RhoA activation relative to Rac1/Cdc42, along with GC collapse, impaired axonal transport, altered neuronal circuits, and cognitive deficits. Balancing RhoGTPase activity using a pharmacologic inhibitor of RhoA activation (i.e. TAT-C3) prior to propofol exposure ameliorates neurotoxicity. What is it about mature neurons that makes them less susceptible to neurotoxicity? Caveolin-1 is a membrane scaffolding protein that regulates and balances RhoGTPase signaling. Caveolin-1 expression increases with neuronal maturation. Dr. Pearn's K08 preliminary data suggests Cav1 plays a critical role in susceptibility to anesthetic-mediated neurotoxicity. When neonatal neurons are transfected with a viral vector to increase Cav1 expression, there is protection against PPF mediate alterations in RhoGTPase signaling, GC collapse, and axonal transport. Dr. Pearn will explore how Cav1 regulates RhoGTPase signaling in the presence of PPF (AIM 1). Furthermore, he will explore how Cav1 expression influences GC morphology and axonal transport (AIM 2), along with neuronal circuit connectivity and cognition (AIM 3). These findings may reveal how Cav1 protects against toxicity. As such, will identify potential therapeutic targets and biomarkers that predict susceptibility to anesthetic-mediated neurotoxicity.

摘要 马修·佩恩博士在麻醉剂中介领域确立了自己作为一名有前途的研究人员的地位 神经毒性和轴突运输。他已经获得并完成了为期两年的FAER拨款，调查 RhoGTP酶信号转导、生长锥(GC)塌陷和轴突运输在麻醉相关中的作用 神经毒性。NIH K08的这项提案扩展了他的研究，调查了小窝蛋白-1(Cav1)在 麻醉剂介导的神经毒性。K08奖将为佩恩博士提供资金和保护时间 需要完成以下目标：(1)成为洞穴1号生物学研究的专家，(2)进一步 推进科技写作，增加第一作者稿量；(3)学习实验室管理 和领导技能，(4)成功获得独立资金，(5)发展成为独立的 临床医生兼科学家。为了实现这些目标，佩恩博士组建了一个由佩恩博士组成的指导团队。 血脉帕特尔和皮尤什·帕特尔医生。 生长锥体塌陷和轴突运输被认为是神经元发育的关键 和认知力。GC形态和轴突运输都受到肌动蛋白动力学的影响，而肌动蛋白动力学又是 受RhoGTPase信号的影响。佩恩博士已经证明，暴露于异丙酚(PPF)的新生神经元 增加了RhoA相对于rac1/cc42的激活，伴随着GC的崩溃，轴突运输受损， 神经元回路改变，以及认知缺陷。使用药物抑制剂平衡RhoGTP酶活性 异丙酚暴露前应用RhoA激活(即TAT-C3)可减轻神经毒性。成熟是什么？ 让神经元更不容易受到神经毒性的影响？小窝蛋白-1是一种膜支架蛋白， 调节和平衡RhoGTPase信号。小窝蛋白-1的表达随着神经元的成熟而增加。Dr。 佩恩的K08初步数据表明，Cav1在麻醉剂介导的敏感性中起着关键作用 神经毒性。当将病毒载体导入新生神经元以增加Cav1的表达时， 对PPF的保护介导了RhoGTPase信号的改变、GC崩溃和轴突运输。Dr。 佩恩将探索Cav1如何在PPF存在的情况下调节RhoGTPase信号(AIM 1)。此外，他还 我将探索Cav1的表达如何影响GC的形态和轴突运输(AIM 2)，以及神经元 电路连通性和认知(目标3)。这些发现可能揭示Cav1是如何防御毒性的。AS 这将确定潜在的治疗靶点和生物标记物，预测麻醉媒介的易感性。 神经毒性。

项目成果

The Effect of Clevidipine on Cerebral Blood Flow Velocity and Carbon Dioxide Reactivity in Human Volunteers.

氯维地平对人类志愿者脑血流速度和二氧化碳反应性的影响。

• DOI: 10.1097/ana.0000000000000236
• 发表时间: 2016
• 期刊: Journal of neurosurgical anesthesiology
• 影响因子: 3.7
• 作者: Lemkuil,BrianP;Gierl,BrianT;Patel,PiyushM;Pearn,MatthewL;Nguyen,LiemC;Minokadeh,Anushirvan;Drummond,JohnC
• 通讯作者: Drummond,JohnC