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

• 批准号: 9293864
• 负责人: Chris G Dulla
• 金额: $ 49.45万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293864
• 关键词: APC gene; Address; Adenomatous Polyposis Coli; Adhesions; Adult; Adverse effects; Aftercare; Age; Age-Months; Alleles; Animal Model; Animals; Attenuated; Behavior; Behavioral; Blood; Brain; Brain region; Breeding; Caring; Child; Childhood; Clinical; Cognition; Communication; Complex; Data; Development; Developmental Delay Disorders; Dose; Drug Kinetics; Early treatment; Electroencephalography; Epilepsy; Excitatory Synapse; Exhibits; Family; Female; Functional disorder; Gene Family; Genes; Genetic Models; Genetic Transcription; Head and neck structure; Hippocampus (Brain); Human; Human Characteristics; Impaired cognition; Infantile spasms; Knock-out; Lead; Life; Limb structure; Link; LoxP-flanked allele; Mediating; Modeling; Molecular; Mus; Mutation; N-Cadherin; Neonatal; Neurologic; Neurons; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phenocopy; Phenotype; Predisposition; Prevention; Property; Regimen; Rodent Model; Role; Seizures; Signal Pathway; Signal Transduction; Spasm; Synapses; Syndrome; Tankyrase; Testing; Therapeutic; Vertebral column; adverse outcome; beta catenin; brain cell; calmodulin-dependent protein kinase II; cell type; density; developmental disease; excitatory neuron; genetic linkage; hippocampal pyramidal neuron; in vivo; inhibitor/antagonist; insight; male; mouse model; neonatal brain; neonate; new therapeutic target; novel; offspring; overexpression; post stroke; pre-clinical; prevent; promoter; recombinase; research study; therapeutic target; therapy design; treatment strategy

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 between 4-8 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 ß-catenin/Wnt pathway. APC is part of the ß-catenin destruction complex, targeting ß-catenin for degradation. When APC is lost, ß-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 from post-natal day 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 are linked to both developmental and seizure disorders. Furthermore, many of the genes linked to IS are either part of the ß-catenin/Wnt pathway or are reciprocally regulated by it. In this proposal we will specifically examine the role of ß-catenin in the pathophysiology of infantile spasms. We will examine the effects of increasing ß-catenin by deleting APC, and independently of APC, on spasms behavior, seizure, and electrographic brain activity. Next, we will perform careful pharmacokinetic, pharmacodynamic, and adverse effect analysis of manipulating ß-catenin during development. Lastly, we will determine if restoring ß-catenin levels to normal attenuates spasms and seizures later in life. This proposal will address the role of ß-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.

项目摘要 婴儿痉挛症（InfantileSpasms，IS，又称West综合征）是一种灾难性的儿童癫痫综合征 以痉挛为特征，在以后的生活中发展为癫痫发作。痉挛的典型症状是 头部、颈部和四肢的屈曲/伸展，发生在4-8个月大之间。目前的治疗 IS的选择通常是无效的，并且与显著的副作用相关。因此，新的治疗 战略至关重要。确定新治疗方法的一个限制因素是缺乏临床前 动物模型我们已经鉴定并表征了具有许多表型的新型啮齿动物模型， 人的特征。该模型是通过饲养含有floxed版本的 大肠腺瘤性息肉病（APC）基因与表达Cre-重组酶基因的雌性小鼠在 控制Ca 2 +/钙调蛋白依赖性蛋白激酶II α（CaMKIIa）启动子。这个的后代 在CaMKIIa阳性神经元中缺乏APC的cross被称为APC条件性敲除（APC cKO）。 APC cKO动物已显示具有增加的兴奋性突触通讯和增加的神经传导。 海马CA 1区锥体神经元兴奋性棘密度。APC是一种主要的抑制性调节因子， 大信号通路称为β-连环蛋白/Wnt通路。APC是β-连环蛋白破坏的一部分， 复合物，靶向β-连环蛋白降解。当APC丢失时，β-连环蛋白水平升高，并且1）增加 一个大家族的基因的转录，和2）增加兴奋性突触的稳定性。我们首先 检查APC cKO动物与人IS一致的表型。我们发现它们表现出 出生后8-11天自发行为痉挛，它们具有与痉挛行为相关的发作EEG 类似于人类在IS中的发作活动，并且作为成年人，他们具有自发的电图和行为 癫痫发作有趣的是，APC杂合突变与发育和癫痫发作障碍有关。 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β-连环蛋白/Wnt通路的一部分。 在这个建议中，我们将专门研究β-连环蛋白在肿瘤病理生理学中的作用。 婴儿痉挛症我们将研究通过删除APC增加β-连环蛋白的影响， APC，痉挛行为，癫痫发作和脑电活动。接下来，我们将认真执行 β-连环蛋白的药代动力学、药效学和不良反应分析 发展最后，我们将确定是否恢复β-连环蛋白水平正常减弱痉挛和癫痫发作 在以后的生活中该提案将解决β-连环蛋白在痉挛的病理生理学中的作用，提供一个新的 用于临床前分析的小鼠模型，并引入了大量新的潜在治疗靶点， 治疗IS。