Wednesday, January 15, 2025
1/15/2025
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.
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