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Epigenetics-Based Autism Treatment with Animal Models and Human Stem Cells

利用动物模型和人类干细胞进行基于表观遗传学的自闭症治疗

基本信息

批准号：
10651463
负责人：
JIAN FENG
金额：
$ 61.57万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651463
关键词：
ASD patient Address Animal Model Autopsy Behavioral Biochemical ChIP-seq Chromatin Corpus striatum structure DNA Sequence Alteration Defect Electrophysiology (science)Enzymes Epigenetic Process Etiology Exhibits Exons Fibroblasts Functional disorder Gene Activation Gene Expression Gene Expression Alteration Genes Genetic Genetic Transcription Genetic study Genomics Glutamates Goals Heterozygote Histones Human Human Genetics Impairment Induced pluripotent stem cell derived neurons Intervention KDM1A gene Large-Scale Sequencing Length Link Lysine Mediating Methylation Modeling Molecular Molecular Abnormality Mus Neurodevelopmental Disorder Neuronal Differentiation Neurons Pathogenicity Patients Phelan-McDermid syndrome Phenotype Play Prefrontal Cortex Proteins Research Risk Factors Role Scaffolding Protein Social Interaction Symptoms Synapses Testing Therapeutic Therapeutic Effect Tissues Transcriptional Regulation Translating Work autism spectrum disorder autistic demethylation drug discovery gene repression genome-wide high risk histone demethylase histone methylation histone methyltransferase histone modification human stem cells induced pluripotent stem cell inhibitor innovation interdisciplinary approach knock-down loss of function mutation mouse model neuronal excitability novel novel therapeutic intervention permissiveness pharmacologic repetitive behavior response risk variant side effect social deficits stem cell differentiation stem cell technology stem cells synaptic function targeted agent targeted treatment transcription factor transcriptome sequencing treatment strategy

项目摘要

Summary This project aims to discover novel pharmacological intervention for core symptoms of autism, including social deficits and repetitive behaviors. One of the causal factors of autism is the loss of Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses. We will use Shank3-deficient mouse models and human stem cell-derived neurons in this drug discovery endeavor. Genetics studies have found that many of genes disrupted in autism are histone-modifying enzymes that mediate histone methylation/demethylation, which play a key role in transcriptional regulation. Our preliminary studies have found that histone lysine 4 dimethylation (H3K4me2, linked to gene activation) is significantly decreased in the prefrontal cortex (PFC) of autistic humans and Shank3-deficient mice. H3K4me2 is demethylated by lysine-specific histone demethylase 1 (LSD1, KDM1A), which is found to be increased in PFC neurons of Shank3-deficient mice. We hypothesize that inhibiting LSD1 to elevate H3K4me2 and restore gene expression may be able to ameliorate autism-like phenotypes, therefore providing a novel therapeutic strategy for autism. Combined behavioral, biochemical, electrophysiological, genomic and stem cell approaches will be used to test this hypothesis. Aim 1, we will characterize epigenetic changes and therapeutic effects of epigenetic agents in mouse models of autism. The alteration of histone methylation marks and histone demethylases will also be examined in PFC of Shank3- deficient mice and autism human postmortem tissues. Aim 2, we will reveal the molecular mechanisms underlying epigenetic treatment of autism models. Synaptic responses and neuronal excitability will be recorded in Shank3-deficient mice treated with LSD1 inhibitors. Genome-wide alteration of gene expression and histone methylation will be examined using RNAseq and ChIPseq. The causal role of identified key molecules in the therapeutic effects of LSD1 inhibitors will also be determined. In Aim 3, we will examine the molecular alteration and treatment strategy in human neurons from ASD patient with Shank3 haploinsufficiency. To find out whether the epigenetic treatment strategy found in Shank3 mouse models might also work in autism patients, we will use the innovative stem-cell technology to examine the capability of LSD1 inhibitors to reverse synaptic deficits and molecular aberrations in ASD patient’s neurons derived from induced pluripotent stem cells. Results from this study will not only reveal the mechanistic link among important autism risk factors, but also uncover a mechanism-based treatment strategy for autism.

总结