The role of beta-catenin in the pathophysiology of infantile spasms

β-连环蛋白在婴儿痉挛症病理生理学中的作用

基本信息

批准号：
10057263
负责人：
Chris G Dulla
金额：
$ 46.05万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057263
关键词：
APC gene Address Adhesions Adult Adverse effects Age Age-Months Alleles Animal Model Attenuated Behavior Behavioral Blood Brain Brain region Breeding Caring Child Clinical Cognitive deficits Communication Complex Data Databases Development Developmental Delay Disorders Dose Drug Kinetics Electroencephalography Enterobacteria phage P1 Cre recombinase Epilepsy Excitatory Synapse Exhibits Family Female Frequencies Functional disorder Future Gene Family Generations Genes Genetic Genetic Transcription Goals Head and neck structure Hippocampus (Brain)Human Human Characteristics Human Genetics Impaired cognition Infantile spasms Knockout Mice Lead Life Limb structure Link LoxP-flanked allele Mediating Modeling Molecular Mus Mutation N-Cadherin Neonatal Neurons Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Phenocopy Phenotype Pre-Clinical Model Predisposition Prevention Regimen Rodent Model Role Seizures Signal Pathway Signal Transduction Spasm Synapses Syndrome System Tankyrase Testing Therapeutic Treatment Protocols Variant Vertebral column WNT Signaling Pathway adverse outcome base beta catenin brain cell calmodulin-dependent protein kinase II cell type childhood epilepsy conditional knockout curative treatments density developmental disease epileptic encephalopathies excitatory neuron experience experimental study hippocampal pyramidal neuron improved outcome in vivo inhibitor/antagonist innovation insight knockout animal male mouse model neonatal brain development neonate new therapeutic target novel offspring overexpression pharmacodynamic model post stroke postnatal pre-clinical promoter risk variant side effect therapeutic target treatment strategy

项目摘要

Project summary Infantile spasms (IS, also known as West Syndrome) is a catastrophic childhood epilepsy syndrome characterized by spasms which progress into seizures later in life. Spasms are typified by spontaneous flexion/extension of the head, neck, and limbs and occur first between 4 and 8 months of age. The current treatment options for IS are often ineffective and are associated with significant side effects. Therefore, novel treatment strategies are essential. One limiting factor in identifying new treatment approaches is a paucity of pre-clinical animal models. We have identified and characterized a novel rodent model with many phenotypic characteristics of human IS. The model was generated by breeding male mice containing a floxed version of the Adenomatous polyposis coli (APC) gene with female mice expressing the Cre-recombinase gene under the control of the Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIa) promoter. The offspring of this cross, which lack APC in CaMKIIa-positive neurons, are known as APC conditional knockouts (APC cKOs). APC cKO animals have been shown to have increased excitatory synaptic communication and an increased density of excitatory spines on hippocampal CA1 pyramidal neurons. APC is the main inhibitory regulator of a large signaling pathway known as the β-catenin/Wnt pathway. APC is part of the β-catenin destruction complex, targeting β-catenin for degradation. When APC is lost, β-catenin levels rise and 1) increase transcription of a large family of genes, and 2) increase the stability of excitatory synapses. We began by examining APC cKO animals for phenotypes consistent with human IS. We found that they exhibit spontaneous behavioral spasms at postnatal days 8-11, they have an ictal EEG correlate of spasm behavior similar to human ictal activity in IS, and as adults, they have spontaneous electrographic and behavioral seizures. Interestingly, APC heterozygous mutations in humans are linked to both developmental and seizure disorders. Furthermore, many of the genes linked to IS are either part of the β-catenin/Wnt pathway or are reciprocally regulated by it. In this proposal, we will specifically examine the role of β-catenin in the pathophysiology of infantile spasms. We will examine the effects of increasing β-catenin (by deleting APC and independently of APC) on spasm behavior, seizures, and electrographic brain activity. Next, we will perform careful pharmacokinetic, pharmacodynamic, and adverse effect analysis of manipulating β-catenin during development with a drug called G007-LK. Lastly, we will determine if restoring β-catenin levels to normal attenuates spasms and seizures later in life. This proposal will address the role of β-catenin in the pathophysiology of spasms, provide a new mouse model for pre-clinical analysis, and introduce a large set of new potential therapeutic targets for the treatment of IS.

项目概要婴儿痉挛症（IS，也称为韦斯特综合症）是一种灾难性的儿童癫痫综合症以痉挛为特征，并在以后的生活中发展为癫痫发作。痉挛的典型特征是自发性痉挛。头部、颈部和四肢的屈曲/伸展首先发生在 4 至 8 个月大的时候。 IS 的治疗方案通常无效并且伴有显着的副作用，因此是新颖的。治疗策略是确定新治疗方法的一个限制因素。我们已经鉴定并表征了一种具有多种表型的新型啮齿动物模型。该模型是通过饲养含有 floxed 版本的雄性小鼠而产生的。腺瘤性结肠息肉病 (APC) 基因与表达 Cre 重组酶基因的雌性小鼠 Ca2+/钙调蛋白依赖性蛋白激酶 II α (CaMKIIa) 启动子的控制。 CaMKIIa 阳性神经元中缺乏 APC，称为 APC 条件敲除 (APC cKO)。 APC cKO 动物已被证明具有增加的兴奋性突触通讯和增加的海马 CA1 锥体神经元兴奋性棘的密度是 APC 的主要抑制性调节因子。称为 β-连环蛋白/Wnt 通路的大信号通路是 β-连环蛋白破坏的一部分。复合物，以 β-连环蛋白为目标进行降解当 APC 丢失时，β-连环蛋白水平升高并且 1) 增加。一个大基因家族的转录，2）增加兴奋性突触的稳定性。检查 APC cKO 动物的表型与人类 IS 一致，我们发现它们表现出一致的表型。出生后第 8-11 天出现自发行为痉挛，发作期脑电图与痉挛行为相关与 IS 中的人类发作活动相似，并且作为成年人，他们有自发的电图和行为提示，人类 APC 杂合突变与发育和癫痫发作有关。此外，许多与 IS 相关的基因要么是 β-连环蛋白/Wnt 通路的一部分，要么是。在本提案中，我们将具体研究 β-连环蛋白在其中的作用。我们将检查增加 β-连环蛋白的影响（通过删除 APC 和独立于 APC）对痉挛行为、癫痫发作和脑电图活动的影响接下来，我们将进行。仔细分析β-连环蛋白的药代动力学、药效学和不良反应最后，我们将确定是否将β-连环蛋白水平恢复到正常水平。该提案将解决 β-连环蛋白在以后的生活中的作用。痉挛的病理生理学，为临床前分析提供新的小鼠模型，并引入大量治疗 IS 的新的潜在治疗靶点。