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The Huang lab is interested in studying the molecular, cellular, circuit, and behavioral functions of genes involved in autism spectrum disorders (ASDs), neuropsychiatric disorders, and epilepsy. We currently focus on Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS), a pair of childhood neurodevelopmental disorders caused by loss and gain of of Retinoic Acid Induced 1 (RAI1), respectively. Both disorders are associated with intellectual disability, ASD, and neuropsychiatric features. Our top priority is to apply modern molecular and neuroscience techniques to decipher the molecular and neural functions of Rai1 in order to develop disease-modifying therapies for patients in Canada and around the world. Here are some highlights of our original discoveries:
- We generated the first Rai1 conditional knockout mouse model (Rai1-flox mice) and identified the molecular function of Rai1 and specific neuronal substrates underlying neurobehavioral features in SMS mice (Huang WH et al., Neuron, 2016). Using iDISCO+ whole brain clearing and imaging techniques, we found that Rai1 ablation from the Emx1-Cre-lineage cortical excitatory neurons increases expression of the ion channel Cav3.1 and enhances hyperexcitability of the hippocampus dentate gyrus granule cells (Chang YT et al., PNAS, 2022). This is the first in vivo mechanism explaining how SMS brains become hyperexcitable.
- We provide the first in vivo evidence that SMS disease features in mice are reversible by postnatal genetic reactivation of Rai1 (Huang WH et al., PNAS, 2018). Building on this work, we performed AAV/CRISPR activation-mediated gene therapy to increase Rai1 levels in vivo and successfully rescues selective disease features in SMS mice (Chang HC et al., J Biol Chem., 2022).
- We developed the first successful neurotrophic factor gene therapy that fully rescues social deficits, obesity, and metabolic features in SMS mice by genetically increasing Bdnf signaling (Javed S et al., Hum Mol Genet., 2021).
How does dosage-imbalance of ASD-risk genes impair neural activity, wiring, and circuit function?
To answer this question, we will use modern neuroscience technologies including ex vivo and in vivo electrophysiology, single cell neurobiology, calcium imaging, brain structural and metabolism imaging, viral-mediated circuit tracing, whole brain clearing and imaging, optogenetic, and neurobehavioral assays to study how ASD-risk genes alter neural functions from molecular to behavioral levels
To answer this question, we will use modern neuroscience technologies including ex vivo and in vivo electrophysiology, single cell neurobiology, calcium imaging, brain structural and metabolism imaging, viral-mediated circuit tracing, whole brain clearing and imaging, optogenetic, and neurobehavioral assays to study how ASD-risk genes alter neural functions from molecular to behavioral levels
Identify molecular targets to treat ASD and psychiatric disorders associated with gene dosage imbalance
There are >600 human disorders associated with decreased gene expression (haploinsufficiency). We use cutting-edge CRISPR, genomic, transcriptomic, and proteomic approaches to identify therapeutic targets to correct symptoms associated with gene dosage imbalance to treat ASDs and epilepsy. Potential therapeutic targets include protein stability modifiers, promoters, and downstream targets of the disease-causing genes.
There are >600 human disorders associated with decreased gene expression (haploinsufficiency). We use cutting-edge CRISPR, genomic, transcriptomic, and proteomic approaches to identify therapeutic targets to correct symptoms associated with gene dosage imbalance to treat ASDs and epilepsy. Potential therapeutic targets include protein stability modifiers, promoters, and downstream targets of the disease-causing genes.