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.

项目摘要这是授予旨在了解异常大脑发育和功能的赠款的续签应用神经发育障碍与癫痫合作，并探索具有潜力的临床前救援策略扭转这些异常。神经发育障碍，例如智力残疾和自闭症，通常是合并症与癫痫发作，例如癫痫。最近发现了许多基因的突变引起神经发育障碍与癫痫合并的合并症，提出了常见的病因机制。其中，编码神经元粘附分子的基因非常高度代表。在这里我们建议继续研究该家族的杰出代表CNTNAP2的新型神经元功能，引起智障，自闭症和语言障碍的单基因综合症，并伴有癫痫病。具体而言，我们将研究CNTNAP2外域脱落的神经发育功能（裂解和旁分泌信号传导中细胞外域的释放。根据我们以前的资金期的发现，我们假设CNTNAP2胞外域的特定区域可以调节网络属性和癫痫发作完整小鼠大脑的活性； CNTNAP2-Ecto脱落在人类受试者和小鼠模型中失调神经发育癫痫发作。我们将通过结合分子专业知识来检验这一假设神经生物学，癫痫，蛋白质组学和药理学，使用动物模型和人类临床CSF样本，以及通过采用几种尖端方法，在以下具体目的中：1）映射结构 CNTNAP2-ECTO函数的决定因素。 2）表征cntnap2-ecto对网络和癫痫发作的影响小鼠的活性。 3）探索在CSF中检测到的棚外生域与癫痫发作活性之间的关系。在基本层面上，生成的数据将为神经元的旁分泌信号的生物学提供新的见解脑发育过程中神经元网络活性的新型机制。从长远来看，我们的研究将提供对癫痫和癫痫发生变化的分子基础的新见解。神经发育障碍，并有可能为新型治疗的临床前原则证明开发性癫痫发作疾病的干预策略。