Exploring the role of oxytocin in the regulation of neuronal excitability

探索催产素在神经元兴奋性调节中的作用

基本信息

批准号：
10397642
负责人：
Andrew P Escayg
金额：
$ 47.42万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397642
关键词：
Active Biological Transport Acute Address Adverse effects Anatomy Animals Antiepileptic Agents Antiinflammatory Effect Behavioral Blood - brain barrier anatomy Brain Brain region Cells Childhood Cholinergic Receptors Clinical Cognitive Data Development Developmental Delay Disorders Disease Encapsulated Encephalopathies Epilepsy Exhibits Febrile Convulsions Formulation Functional disorder Goals Hippocampus (Brain)Intellectual functioning disability Interneurons Ion Channel Knowledge Lead Life Literature Mediating Modeling Mutant Strains Mice Mutation Neurons Neuropeptides Oxytocin Patients Penetrance Pharmacological Treatment Pharmacology Phenotype Predisposition Property Proteins Publishing Recurrence Regulation Reporting Resistance Role SCN8A encephalopathy SCN8A gene Seizures Social Behavior Sodium Channel Suggestion Synapses Technology Testing Therapeutic Variant autism spectrum disorder base behavioral phenotyping biomaterial compatibility cell type childhood epilepsy clinical application clinically relevant dravet syndrome drug candidate experimental study gain of function gamma-Aminobutyric Acid improved loss of function loss of function mutation mortality mouse model mutant nanoformulation nanoparticle nanoparticle delivery nervous system disorder neural circuit neuronal excitability neuropeptide Y novel patch clamp protective effect rabies virus glycoprotein G receptor side effect social social deficits transcytosis voltage

Active Biological Transport Acute Address Adverse effects Anatomy Animals Antiepileptic Agents Antiinflammatory Effect Behavioral Blood - brain barrier anatomy Brain Brain region Cells Childhood Cholinergic Receptors Clinical Cognitive Data Development Developmental Delay Disorders Disease Encapsulated Encephalopathies Epilepsy Exhibits Febrile Convulsions Formulation Functional disorder Goals Hippocampus (Brain)Intellectual functioning disability Interneurons Ion Channel Knowledge Lead Life Literature Mediating Modeling Mutant Strains Mice Mutation Neurons Neuropeptides Oxytocin Patients Penetrance Pharmacological Treatment Pharmacology Phenotype Predisposition Property Proteins Publishing Recurrence Regulation Reporting Resistance Role SCN8A encephalopathy SCN8A gene Seizures Social Behavior Sodium Channel Suggestion Synapses Technology Testing Therapeutic Variant autism spectrum disorder base behavioral phenotyping biomaterial compatibility cell type childhood epilepsy clinical application clinically relevant dravet syndrome drug candidate experimental study gain of function gamma-Aminobutyric Acid improved loss of function loss of function mutation mortality mouse model mutant nanoformulation nanoparticle nanoparticle delivery nervous system disorder neural circuit neuronal excitability neuropeptide Y novel patch clamp protective effect rabies virus glycoprotein G receptor side effect social social deficits transcytosis voltage

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项目摘要

PROJECT SUMMARY Dysfunction of voltage-gated sodium channels (VGSCs) is responsible for several forms of catastrophic childhood encephalopathies. Over 1000 loss-of-function mutations in the VGSC SCN1A have been identified during the last two decades and are the main cause of Dravet syndrome (DS), characterized by recurrent early- life febrile seizures (FSs), severe afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. Mutations in the VGSC SCN8A were more recently identified in 2012, and already over 200 gain-of-function SCN8A mutations have been reported in patients with a range of clinical features including catastrophic treatment-resistant childhood epilepsy, autism, intellectual disability and developmental delay. Unfortunately, most anti-epileptic drugs (AEDs) fail to adequately treat the broad range of severe seizures and behavioral phenotypes in patients with SCN1A- and SCN8A-derived epilepsy. Thus, despite recent progress in pharmacological treatments for DS, there remains a need to develop more effective, longer lasting treatments with fewer side effects. Neuropeptides are well known in animal studies to show great promise for controlling seizures and ameliorating behavioral abnormalities; however, they do not readily cross the blood brain barrier and are rapidly metabolized when given systemically. Thus, poor brain penetrance is a critical barrier to the clinical application of these promising therapeutics. To overcome this challenge, we developed and validated an approach based on the encapsulation of neuropeptides in nanoparticles conjugated to rabies virus glycoprotein (RVG). Using this approach, we have found that intranasal delivery of nanoparticle-encapsulated oxytocin (NP- OT) greatly increases brain penetrance and the capacity of OT to confer robust and sustained increases in resistance to seizures in mouse models of SCN1A and SCN8A dysfunction. We have also extended our strategy to encapsulate neuropeptide Y (NP-NPY), and similarly observed a robust improvement in its ability to confer seizure resistance. In the proposed study, we will establish the ability of NP-OT and NP-NPY to ameliorate spontaneous seizures and behavioral abnormalities in Scn1a and Scn8a mouse mutants (Aim 1). While the role of OT in social behavior is well-studied, less is known about the mechanisms by which it modulates seizure susceptibility. Thus, we will also identify the cellular and neural circuit mechanisms that contribute to the ability of OT to increase seizure resistance in the Scn1a and Scn8a mutants (Aim 2). Our long-term goal is to develop safe and effective approaches for the brain delivery of neuropeptides for the treatment of epilepsy and other neurological disorders.

项目摘要电压门控钠通道（VGSC）的功能障碍导致了几种形式的灾难性儿童脑病。已经确定了VGSC SCN1A的1000多个功能丧失突变在过去的二十年中，是Dravet综合征（DS）的主要原因，其特点是生命高温癫痫发作（FSS），严重的Afebrile癫痫，认知和行为缺陷以及15-20％的死亡率速度。 VGSC SCN8A中的突变最近在2012年被发现，并且已经超过200个功能据报道，具有一系列临床特征的患者，包括灾难性的患者SCN8A突变耐药的儿童癫痫，自闭症，智力残疾和发育延迟。很遗憾，大多数抗癫痫药（AED）无法充分治疗广泛的严重癫痫发作和行为 SCN1A和SCN8A衍生癫痫患者的表型。因此，尽管最近取得了进展 DS的药理治疗方法，仍然需要开发更有效，更持久的治疗方法副作用较少。神经肽在动物研究中是众所周知的，可以显示出控制的巨大希望癫痫发作和改善行为异常；但是，它们不容易越过血脑屏障并在系统地给出时会迅速代谢。因此，脑部渗透不良是对这些有希望的治疗剂的临床应用。为了克服这一挑战，我们开发了一个基于与狂犬病病毒糖蛋白结合的纳米颗粒中神经肽的封装方法（RVG）。使用这种方法，我们发现纳米颗粒封装的催产素的鼻内递送（NP- ot）大大增加了大脑的渗透率以及OT赋予强大和持续增加的能力 SCN1A和SCN8A功能障碍的小鼠模型中癫痫发作的抗性。我们还扩展了战略封装神经肽Y（NP-NPY），同样观察到其赋予能力的强大改善癫痫发作性。在拟议的研究中，我们将建立NP-OT和NP-NPY改善的能力 SCN1A和SCN8A小鼠突变体中的自发癫痫发作和行为异常（AIM 1）。而角色社会行为中的OT是经过充分研究的，对调节癫痫发作的机制知之甚少敏感性。因此，我们还将确定有助于能力的细胞和神经回路机制 OT增加了SCN1A和SCN8A突变体中癫痫发作的耐药性（AIM 2）。我们的长期目标是发展安全有效的方法，用于脑部递送神经肽用于治疗癫痫和其他神经系统疾病。