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Adhesion molecules and developmental epilepsy disorders

粘附分子与发育性癫痫病

基本信息

批准号：
10592736
负责人：
Peter Penzes
金额：
$ 54.49万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2017-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592736
关键词：
Affect Affinity Chromatography Animal Model Binding Biological Biological Assay Biology Brain Calcium Cell Adhesion Molecules Cerebrospinal Fluid Child Clinical Cortical Dysplasia Data Dendritic Spines Development Disease Electroencephalography Enzyme-Linked Immunosorbent Assay Epilepsy Etiology Extracellular Domain Family Funding Future Genes Genetic Grant Hippocampus (Brain)Human Image Inherited Injections Intellectual functioning disability Intervention Language Disorders Maps Mass Spectrum Analysis Membrane Proteins Methodology Molecular Molecular Neurobiology Mus Mutation Neurodevelopmental Disorder Neurons Oligopeptides Paracrine Communication Partial Epilepsies Pathogenesis Pathogenicity Patients Peptides Pharmacology Phenotype Pitt-Hopkins syndrome Property Proteomics Pump Recombinants Regulation Research Project Grants Role Sampling Seizures Severities Slice Specificity Syndrome Tertiary Protein Structure Testing Therapeutic Western Blotting Wild Type Mouse autism spectrum disorder base brain abnormalities comorbidity contactin dravet syndrome genetic association human subject improved in vivo imaging insight language impairment mouse model multi-photon neurotransmission novel novel therapeutic intervention pre-clinical

项目摘要

PROJECT SUMMARY This is a renewal application for a grant aimed to understand abnormal brain development and function in neurodevelopmental disorders co-morbid with epilepsy, and to explore preclinical rescue strategies with the potential of to reverse these abnormalities. Neurodevelopmental disorders, such as intellectual disability and autism are often comorbid with seizure disorders, such as epilepsy. Mutations in a number of genes have recently been discovered which cause neurodevelopmental disorders comorbid with epilepsy, suggesting common etiological mechanisms. Among these, genes encoding neuronal adhesion molecules are very highly represented. Here we propose to continue to investigate novel neuronal functions of a prominent representative of this family, CNTNAP2, mutations in which cause monogenic syndromes of intellectual disability, autism, and language disorder, comorbid with epilepsy. Specifically, we will investigate the neurodevelopmental functions of CNTNAP2 ectodomain shedding (cleavage and release of the extracellular domain) in paracrine signaling. Based on our findings from the previous funding period, we hypothesize that specific regions on CNTNAP2's ectodomain can modulate network properties and seizure activity in the intact mouse brain; CNTNAP2-ecto shedding is dysregulated in human subjects with and mouse models of neurodevelopmental seizure disorders. We will test this hypothesis by combining expertise in molecular neurobiology, epilepsy, proteomics, and pharmacology, using animal models and human clinical CSF samples, and by employing several cutting-edge methodologies, in the following Specific Aims: 1) To map the structural determinants of CNTNAP2-ecto function. 2) To characterize the impact of CNTNAP2-ecto on network and seizure activity in mice. 3) To explore the relationship between shed ectodomains detected in the CSF and seizure activity. On a basic level, data generated will provide new insights into the biology of paracrine signaling by neuronal ectodomain shedding and reveal novel mechanisms of regulation neuronal network activity during brain development. In the long run, our studies will provide novel insight into the molecular basis of alterations in both epilepsy and neurodevelopmental disorders and have the potential to provide preclinical proof-of-principle for novel therapeutic strategies for interventions in developmental seizure disorders.

项目总结这是一项旨在了解脑部异常发育和功能的基金的续期申请。神经发育障碍与癫痫共病的临床前抢救策略探讨来扭转这些反常现象。神经发育障碍，如智力残疾和自闭症，通常与癫痫等癫痫发作障碍并存。最近发现了许多基因的突变。这会导致神经发育障碍并伴有癫痫，这表明了常见的病因机制。其中，编码神经元黏附分子的基因具有很高的代表性。在此，我们建议继续研究这个家族的一个重要代表CNTNAP2突变的新神经元功能这会导致智力残疾、自闭症和语言障碍等单基因综合征，并与癫痫并存。具体地说，我们将研究CNTNAP2胞外结构域脱落(裂解和细胞外域的释放)旁分泌信号。根据我们在前一个资助期的调查结果，我们假设CNTNAP2的S胞外区上的特定区域可以调节网络特性和癫痫发作在完整的小鼠脑中的活动；CNTNAP2-ecto的脱落在人类和小鼠模型中是失调的神经发育性癫痫。我们将结合分子方面的专业知识来检验这一假说。神经生物学、癫痫、蛋白质组学和药理学，使用动物模型和人类临床脑脊液样本，以及通过采用几种尖端方法，在以下具体目标中：1)绘制结构图 CNTNAP2-ecto功能的决定因素。2)表征CNTNAP2-ecto对网络和癫痫发作的影响小鼠的活动。3)探讨脑脊液中脱落胞外区与癫痫发作活动的关系。在基础水平上，产生的数据将为神经元旁分泌信号的生物学提供新的见解胞外区的脱落，揭示了大脑发育过程中调节神经元网络活动的新机制。从长远来看，我们的研究将为癫痫和癫痫的分子基础提供新的见解。神经发育障碍，有可能为新的治疗方法提供临床前的原则证据发育性癫痫障碍的干预策略。