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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：
10308043
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/10308043
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 inhibitor therapy 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.

项目总结