Neuronal excitability and copy number variation disorders

神经元兴奋性和拷贝数变异障碍

基本信息

批准号：
10626765
负责人：
Peter Penzes
金额：
$ 64.82万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626765
关键词：
16p11.2 Affect Agreement Antiepileptic Agents Antineoplastic Agents BIK gene Bioinformatics Biological Brain Cell membrane Cells Child Chromosome 16 Chromosomes Complement Complex Copy Number Polymorphism Data Development Disease Drug Targeting Epilepsy Equilibrium Etiology FDA approved Future Genes Genetic Genomic DNA Genotype High Prevalence Human Individual Induced pluripotent stem cell derived neurons Intellectual functioning disability Investigation Ion Channel Knowledge Membrane Mendelian disorder Methodology Modeling Molecular Mus NIH Program Announcements Neurobiology Neurodevelopmental Disorder Neurons Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Pharmacology Phenotype Physiology Play Predisposition Prevalence Process Property Proteins Proteome Proteomics Recurrence Regulation Relative Risks Research Risk Risk Factors Role SNAP receptor Seizures Signal Transduction Site Synapses Synaptic Receptors Synaptic Transmission Synaptosomes Therapeutic Work anti-cancer autism spectrum disorder childhood epilepsy clinical phenotype comorbidity drug repurposing effective therapy excitatory neuron genetic architecture induced pluripotent stem cell inhibitory neuron innovation insight mouse model multidisciplinary network dysfunction neuronal excitability neuroproteomics novel novel strategies pharmacologic protein protein interaction receptor stem cell model stem cells superresolution imaging superresolution microscopy therapeutic development trafficking treatment strategy

项目摘要

ABSTRACT Copy number variations (CNVs) are a major cause of neurodevelopmental disorders, but their biological investigation and pharmacological targeting pose many challenges. Deletions locus are among the most frequent causes of autism spectrum disorder and duplications at the 16p11.2 (ASD). However, alterations in the corresponding protein networks, especially at key cellular sites for pathogenesis, have not been investigated in this or other CNVs. We propose to use compartment-specific neuroproteomics, combined with bioinformatics, super-resolution microscopy, and drug repurposing, to understand and alter dendritic excitability phenotypes in 16p11.2 mouse and induced pluripotent stem cell (iPSC) models. Based on our extensive preliminary data, we hypothesize that altered expression of PRRT2, which likely regulates the trafficking of a subset of ion channels and receptors, drives and abnormal complement of ion channels and receptor on the plasma membrane, leading to abnormal excitability, excitatory/inhibitory (E/I) balance, and network properties in 16p11.2 models and patients. These phenotypes may be reversed by targeting ion channel function using FDA- approved anti-epileptic drugs or ERK signaling using repurposed cancer drugs. Our collaborative team, which includes experts in neurodevelopmental disorders (Penzes), neuroproteomics (Savas), molecular pharmacology (Barbolina), and ion channel physiology (George) will employ a powerful and multidisciplinary combination of highly innovative methodologies to pursue the following Specific Aims: (1) To chart the developmental regulation and determine molecular mechanisms underlying abnormal excitability in dup and del mice and human neurons. (2) To chart the developmental profile and determine the molecular mechanisms underlying the role of PRRT2 as a driver of excitability and seizure phenotypes. (3) Pharmacological reversal of 16p11.2 del and dup phenotypes. This proposal will be the first to demonstrate that cellular subcompartment-specific proteomics combined with super-resolution microscopy, informed by highly penetrant monogenic disease genes within a CNV, can identify novel disease mechanisms. Such phenotypes could be reversed globally by targeting network hubs using repurposed drugs, opening novel strategies for the treatment of neurodevelopmental disorders.

抽象的拷贝数变化（CNV）是神经发育障碍的主要原因，但它们的生物学调查和药理靶向构成许多挑战。删除基因座是之中这最多频繁原因的自闭症光谱紊乱和重复16p11.2 （ASD）。但是，改变尚未在此或其他CNV。我们建议使用隔室特异性神经蛋白质组学，并结合生物信息学，超分辨率显微镜和药物重新利用，以理解和改变树突状兴奋性表型在16p11.2小鼠和诱导的多能干细胞（IPSC）模型中。根据我们广泛的初步数据我们假设PRRT2的表达改变了，这可能调节离子子集的运输血浆上离子通道和受体的通道和受体，驱动器和异常补体膜，导致异常兴奋性，兴奋/抑制（E/I）平衡和网络属性 16p11.2型号和患者。这些表型可以通过使用FDA-靶向离子通道函数来逆转使用再利用的癌症药物批准的抗癫痫药或ERK信号传导。我们的合作团队包括神经发育障碍（PENZES），神经蛋白质组学（SAVAS），分子药理学专家（Barbolina）和离子频道生理学（George）将采用强大而多学科的组合高度创新的方法来追求以下特定目的：（1）绘制发展性调节并确定DUP和DEL小鼠中异常兴奋性的基本机制，人神经元。（2）绘制发展曲线并确定基础机制 PRRT2作为兴奋性和癫痫发作表型的作用。（3）16p11.2 del的药理逆转和DUP表型。该提案将是第一个证明细胞子组特定的一个提案蛋白质组学结合了超分辨率显微镜，由高度渗透性单基因疾病告知 CNV内的基因可以鉴定新的疾病机制。这样的表型可以通过使用重新利用的药物靶向网络中心神经发育障碍。