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.

抽象的拷贝数变异 (CNV) 是神经发育障碍的主要原因，但其生物学特性研究和药理学靶向提出了许多挑战。删除轨迹是之中这最多经常的原因的自闭症光谱紊乱以及 16p11.2 的重复（自闭症谱系障碍）。然而，改变相应的蛋白质网络，特别是在发病机制的关键细胞位点，尚未得到研究这个或其他 CNV。我们建议使用区室特异性神经蛋白质组学，结合生物信息学，超分辨率显微镜和药物再利用，以了解和改变树突兴奋性表型在 16p11.2 小鼠和诱导多能干细胞 (iPSC) 模型中。根据我们广泛的初步数据，我们假设改变了 PRRT2 的表达，这可能调节离子子集的运输离子通道和受体、等离子体上离子通道和受体的驱动和异常补充膜，导致异常的兴奋性、兴奋性/抑制性（E/I）平衡和网络特性 16p11.2 模型和患者。这些表型可以通过使用 FDA-靶向离子通道功能来逆转批准的抗癫痫药物或使用重新利用的癌症药物的 ERK 信号传导。我们的协作团队，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）和离子通道生理学（George）将采用强大的多学科组合高度创新的方法，以实现以下具体目标： (1) 绘制发展图表调节和确定 dup 和 del 小鼠异常兴奋性的分子机制人类神经元。 (2) 绘制发育概况并确定潜在的分子机制 PRRT2 作为兴奋性和癫痫表型驱动因素的作用。 (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室特定的蛋白质组学与超分辨率显微镜相结合，由高渗透性单基因疾病提供信息 CNV 内的基因可以识别新的疾病机制。这种表型可以通过以下方式在全球范围内逆转使用重新调整用途的药物瞄准网络中心，开辟新的治疗策略神经发育障碍。