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Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders

利用新发现的 EZH1 相关综合征探索神经发育障碍的药理恢复

基本信息

批准号：
10528056
负责人：
Naiara Aquizu Lopez
金额：
$ 28.61万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528056
关键词：
Active Sites Affect Binding Binding Sites Biological Biological Assay Brain Brain Diseases Cell Culture Techniques ChIP-seq Child Chromatin Chromatin Remodeling Factor Cognitive Computing Methodologies Cysteine DNA biosynthesis Data Defect Development Differentiated Gene Disease EZH2 gene Enhancers Ensure Enzymes Epigenetic Process Evaluation Face Fibroblasts Gene Expression Gene Silencing Genes Goals Heterozygote Histologic Histone H3 Histones Homeostasis Homologous Gene Human Impairment Intellectual functioning disability Intervention Language Libraries Lysine Malignant Neoplasms Mediating Methylation Missense Mutation Mitosis Molecular Motor Mutation Nerve Degeneration Neurites Neurodevelopmental Disorder Neuronal Differentiation Neurons Organoids Pathogenesis Pathogenicity Pathway interactions Patients Pharmacological Treatment Pharmacology Phenotype Positioning Attribute Prosencephalon Recovery Recurrence Regulation Reproducibility Resources Running Social Behavior Symptoms Synapses Syndrome Technology Testing Therapeutic Tissues Variant Western Blotting Work alternative treatment autism spectrum disorder base cell type chromatin modification design disability gain of function gain of function mutation gene repression genome-wide histone methyltransferase human disease human embryonic stem cell in vitro Assay in vitro testing inhibitor nerve stem cell neurodevelopment neuroregulation novel novel therapeutic intervention premature spatiotemporal therapeutic evaluation therapeutic target transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are a group of conditions that affect brain development and function often leading to lifelong impairments in motor, language, cognitive and/or social behaviors. Increasing evidence involve chromatin regulation in the pathogenic mechanism of neurodevelopmental disorders (NDDs), such as autism and intellectual disabilities. Importantly, chromatin regulators constitute an attractive group for pharmacological intervention given that most harbor enzymatic activities or well-defined binding domains that can be targeted. The overarching goal of this proposal is to identify and test the therapeutic potential of a novel class of chromatin regulator compounds. In particular our work will be focused on a NDD caused by EZH1 gain of function (GOF) mutations that we have recently identified. EZH1, and its paralogue EZH2, catalyze histone H3 Lysine 27 methylation, a chromatin modification that marks and maintains transcriptional repression. Based on our preliminary data we propose the hypothesis that the NDD in these patients is caused by dysregulation of H3K27 methylation leading to abnormal transcriptional repression of neuronal differentiation genes. Thus, we envision a unique opportunity for pharmacological treatment of this patients using EZH inhibitors. To test this hypothesis, we will dissect cellular and molecular mechanisms affected by EZH1 GOF mutations during neuronal differentiation (Aim 1) and identify EZH1 inhibitors with potential to restore neurodevelopmental defects caused by EZH1 GOF mutations (Aim 2). Results obtained here will serve as a proof of principle for the use of EZH inhibitors to treat NDDs caused by EZH1 GOF mutations and potentially extend their application to other NDDs with altered EZH1/2 and H3K27me3 mediated transcriptional repression.

项目概要/摘要神经发育障碍 (NDD) 是一组经常影响大脑发育和功能的疾病导致运动、语言、认知和/或社交行为的终生障碍。越来越多的证据涉及自闭症等神经发育障碍 (NDD) 致病机制中的染色质调节和智力障碍。重要的是，染色质调节剂构成了药理学上有吸引力的群体鉴于大多数都具有酶活性或明确的可靶向结合域，因此需要进行干预。该提案的总体目标是识别和测试一类新型染色质的治疗潜力调节剂化合物。我们的工作将特别关注由 EZH1 功能增益 (GOF) 引起的 NDD 我们最近发现的突变。 EZH1 及其旁系同源物 EZH2 催化组蛋白 H3 赖氨酸 27 甲基化，一种标记并维持转录抑制的染色质修饰。基于我们的初步数据我们提出假设，这些患者的 NDD 是由 H3K27 失调引起的甲基化导致神经元分化基因的异常转录抑制。因此，我们设想这是使用 EZH 抑制剂对这些患者进行药物治疗的独特机会。为了检验这个假设，我们将剖析神经元发育过程中受 EZH1 GOF 突变影响的细胞和分子机制分化（目标 1）并鉴定 EZH1 抑制剂有可能恢复引起的神经发育缺陷由 EZH1 GOF 突变引起（目标 2）。此处获得的结果将作为 EZH 使用的原理证明抑制剂治疗由 EZH1 GOF 突变引起的 NDD，并有可能将其应用扩展到其他领域 EZH1/2 和 H3K27me3 改变的 NDD 介导转录抑制。