Projects

What are we working on right now?

The Impact Of Environmental Factors On Fetal Brain Development

Neurodevelopment is a complex and highly regulated process, vulnerable to disruption by various external factors. Exposure to harmful substances during pregnancy can have lasting consequences on brain development, leading to neurodevelopmental disorders or impaired cognitive function. To investigate how these environmental factors impact early brain development, we use cortical brain organoids as a model system. Our approach is multifaceted, examining molecular, cellular, structural, and functional changes that arise from fetal exposure to common environmental substances. By studying these changes, our goal is to understand how such exposures may alter the trajectory of fetal brain growth and development, potentially leading to long-term deficits in neural function and connectivity.






Cortical organoid models of autism

Organoid models provide a powerful platform to recapitulate brain development in vitro, making them excellent tools for studying neurodevelopmental disorders. We currently use these models to investigate genetic mutations linked to autism, focusing on how these mutations affect cortical development, as autism predominantly impacts the cortex. By leveraging a range of molecular, cellular, and functional assays, our aim is to unravel the mechanisms by which these mutations disrupt neurodevelopment. Ultimately, this approach will help us identify potential therapeutic strategies to mitigate the effects of autism-related mutations and improve outcomes for affected individuals.






Improving Variant Effect Predictors using Tissue Specific Splicing Isoform Expression

This project introduces a cutting-edge approach to variant interpretation by integrating tissue-specific transcript expression with pathogenicity predictions. This unique framework empowers researchers and clinicians to identify and prioritize variants based on their tissue-specific impact, addressing gaps in traditional methods. exTSP (expression-based Tissue-Specific Pathogenicity) is a scoring system that evaluates how genetic variants affect transcripts expressed in specific tissues. By focusing on isoform expression, exTSP enhances our understanding of disease-related variants and their tissue-specific consequences. There are a variety of use cases:

  • Improve Variant Interpretation: Moves beyond generic pathogenicity predictors by considering the tissue context, offering insights into Variants of Uncertain Significance (VUS).
  • Disease-Relevant Genes: Highlights genes whose variants impact transcripts expressed in tissues critical to the disease.
  • Guide Experiments: Helps researchers focus on variants with the highest potential for functional impact.






    • Mouse Models Of Neurodevelopmental Disorders

    CUL3

    Rare and de novo single nucleotide variants (SNVs) are major risk factors for Autism Spectrum Disorders (ASD). The majority of ASD-associated SNVs affect a single allele of a gene, leading to haploinsufficiency. Correcting haploinsufficiency by increasing the expression level of the deficient allele could provide an attractive strategy for ASD treatment. A variant of CRISPR, CRISPRa (CRISPR activation), offers the possibility to correct haploinsufficiency by targeting gene promoters and/or enhancers to increase the wild-type allele’s expression. We aim to use CRISPRa to upregulate Cul3 ubiquitin ligase, a high confidence risk gene for ASD. We have generated a haploinsufficient Cul3+/- mouse model and observed multiple brain morphological, molecular, and behavioral phenotypes. We hypothesize that upregulation of Cul3 early in development with CRISPRa can rescue observed phenotypes and can lay the foundation for therapeutic interventions in ASDs.