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

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.

项目概要电压门控钠通道 (VGSC) 的功能障碍是导致多种形式的灾难性疾病的原因儿童脑病。 VGSC SCN1A 中已发现超过 1000 个功能丧失突变是过去二十年中出现的 Dravet 综合征 (DS) 的主要原因，其特征是反复发作的早期- 终生热性惊厥 (FSs)、严重非热性癫痫、认知和行为缺陷以及 15-20% 的死亡率速度。 VGSC SCN8A 的突变于 2012 年被发现，并且已经有超过 200 种功能获得性突变据报道，具有一系列临床特征的患者存在 SCN8A 突变，包括灾难性的难治性儿童癫痫、自闭症、智力障碍和发育迟缓。很遗憾，大多数抗癫痫药物 (AED) 无法充分治疗广泛的严重癫痫发作和行为问题 SCN1A 和 SCN8A 衍生性癫痫患者的表型。因此，尽管最近在 DS 的药物治疗，仍然需要开发更有效、更持久的治疗方法副作用更少。众所周知，神经肽在动物研究中显示出控制疾病的巨大前景。癫痫发作和改善行为异常；然而，它们不容易穿过血脑屏障全身给药后会迅速代谢。因此，较差的大脑渗透率是实现这一目标的关键障碍。这些有前途的疗法的临床应用。为了克服这一挑战，我们开发并验证了基于将神经肽封装在与狂犬病病毒糖蛋白缀合的纳米颗粒中的方法（RVG）。使用这种方法，我们发现纳米颗粒封装的催产素（NP- OT）极大地提高了大脑渗透率以及 OT 带来强劲和持续增长的能力 SCN1A 和 SCN8A 功能障碍小鼠模型对癫痫发作的抵抗力。我们还扩展了我们的策略封装神经肽 Y (NP-NPY)，并且类似地观察到其赋予能力的强劲改善癫痫抵抗。在拟议的研究中，我们将建立 NP-OT 和 NP-NPY 改善症状的能力 Scn1a 和 Scn8a 小鼠突变体的自发性癫痫发作和行为异常（目标 1）。虽然角色 OT 在社会行为中的作用已得到充分研究，但对其调节癫痫发作的机制知之甚少易感性。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 Scn1a 和 Scn8a 突变体的癫痫抵抗力（目标 2）。我们的长期目标是发展安全有效的脑部递送神经肽治疗癫痫和其他疾病的方法神经系统疾病。