The role of caveolin-1 on anesthetic-mediated neurotoxicity

摘要 Matthew Pearn博士已经确立了自己作为麻醉介导的领域的一个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两年的FAER赠款，调查 RhoGT3信号传导、生长锥（GC）塌陷和轴突运输在麻醉相关性 神经毒性这项NIH K08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Pearn博士提供资金和保护时间 需要完成以下目标：（1）成为Cav1生物学研究的专家，（2）进一步 提高他的科学写作和增加第一作者手稿的数量，（3）学习实验室管理 和领导技能，（4）成功地获得独立的资金，（5）发展成为独立的 临床科学家为了实现这些目标，Pearn博士组建了一个由Dr. 希玛·帕特尔和皮尤什·帕特尔医生 生长锥塌陷和轴突运输被认为是神经元发育的关键 和认知。GC形态和轴突运输都受到肌动蛋白动力学的影响， 受RhoGT3信号的影响。Pearn博士已经表明，暴露于丙泊酚（PPF）的新生神经元 相对于Rac 1/Cdc 42，RhoA活化增加，沿着GC塌陷，轴突运输受损， 神经回路改变和认知缺陷使用药理学抑制剂平衡RhoGT活性 在丙泊酚暴露之前RhoA激活（即TAT-C3）的降低改善了神经毒性。什么叫成熟 使它们不易受到神经毒性的影响？Caveolin-1是一种膜支架蛋白， 调节和平衡RhoGT3信号传导。Caveolin-1的表达随着神经元的成熟而增加。博士 Pearn的K08初步数据表明Cav 1在麻醉剂介导的易感性中发挥着关键作用 神经毒性当用病毒载体转染新生神经元以增加Cav1表达时， 对PPF介导的RhoGT3信号传导、GC崩溃和轴突运输的改变的保护。博士 Pearn将探索Cav1如何在PPF（AIM 1）存在下调节RhoGT3信号传导。而且他 将探讨Cav1表达如何影响GC形态和轴突运输（AIM 2），沿着神经元 电路连接和认知（AIM 3）。这些发现可能揭示Cav1如何保护免受毒性。作为 这将确定潜在的治疗靶点和预测对麻醉剂介导的药物敏感性的生物标志物。 神经毒性

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.