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.

项目摘要/摘要神经发育障碍（NDDS）是一组影响大脑发育和功能的疾病导致运动，语言，认知和/或社会行为的终身障碍。越来越多的证据涉及神经发育障碍（NDDS）的致病机理中的染色质调节，例如自闭症和智力残疾。重要的是，染色质调节剂构成了药理学的有吸引力的群体鉴于大多数可以针对目标的酶活性或定义明确的结合域的干预措施。该提案的总体目标是识别和测试新型染色质类的治疗潜力调节剂化合物。特别是，我们的工作将集中于EZH1功能增益引起的NDD（GOF）我们最近确定的突变。 EZH1及其旁产EZH2，催化组蛋白H3赖氨酸27 甲基化，一种染色质修饰，标记并保持转录抑制作用。基于我们初步数据我们提出了以下假设：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转录异常抑制。因此，我们设想使用EZH抑制剂对该患者进行药理学治疗的独特机会。为了检验这一假设，我们将在神经元期间剖析受EZH1 GOF突变影响的细胞和分子机制分化（AIM 1）并识别具有恢复神经发育缺陷的潜力的EZH1抑制剂由EZH1 GOF突变（AIM 2）。此处获得的结果将作为使用EZH的原理证明治疗由EZH1 GOF突变引起的NDD的抑制剂，并有可能将其应用扩展到其他 EZH1/2和H3K27ME3介导的转录抑制的NDD变化。