We are grateful for federal, foundation, philanthropic, corporate and institutional sponsorship of past and ongoing research in our laboratory:
Ongoing projects In human cellular modeling of pathogenic variants in neurodevelopmental disorders
1) CHD2: “The cis-regulatory grammar and epigenetic control of human interneuron progenitor specification” NIH NINDS (R01 NS114551) support, White, Zhang, Huettner collaborators. The goal of this work is to define the cis-regulatory grammar that controls transcriptional regulation during the specification of GABAergic inhibitory cortical interneurons. We are also studying how these programs are altered by pathogenic mutations of the chromatin remodeller CHD2, which cause autism and/or epilepsy.
2) MYT1L: “Genomic and functional characterization of ASD and ID-associated MYT1L mutation” NIH NIMH (R01 MH124808, the Jakob Gene Fund, and IDDRC (NICHD U54 HD087011)) support; Dougherty, Maloney co-Is.
We are characterizing the consequences of pathogenic MYT1L mutation on neurodevelopment and function in iPSC and mouse models.
3) ZNF292: “Using human pluripotent stem cell models to define disease mechanisms for ZNF292 variants”. NIH Common Fund/NINDS (U0-HG007530) support. In work supported by the NIH Common Fund/NINDS, we are defining the pathogenicity and phenotypic consequences of a ZNF292 variant present in a patient in the Undiagnosed Diseases Network. We are also modeling additional ZNF292 pathogenic variants present in this patient population and are characterizing mouse models of Znf292 deficiency.
4) Down Syndrome: “Modeling differential cognitive function in Down Syndrome in human pluripotent stem cell models” NICHD (U54 HD087011-S1) support, Bhattacharyya co-I. We are deriving and characterizing new iPSC models of Down Syndrome from deeply phenotyped, cognitively stratified individuals, to identify contributors to differential cognitive function in this patient population.
5) Human Cellular Models Program, IDDRC (P50 HD103525). In work supported by the NICHD (WUSTL IDDRC), we are building and characterizing several new types of iPSC models of neurodevelopmental disorders in collaboration with Joe Dougherty and Chris Gurnett. IDDRC support for pilot studies has underpinned our initiation of many of the modeling efforts shown here.
6) Pathogenic variant screening: “Multi-organism platform for functional assessment of human birth defect associated genomic variants” NIH NICHD R01 HD110556, Schedl, A. Johnson, Solnica-Krezel, Ornitz co-Is, McNeill, Pak, Baldridge collaborators. This project funds our efforts (also pursued under PreMIER) to model the consequences of pathogenic gene variants that cause birth defects and intellectual and developmental disabilities.
7) Brain overgrowth disorders. “Mechanisms of brain overgrowth disorders resulting from mutation of PIK3CA/AKT3 and DNMT3A” Supported by the M-CM Network, an Engelhart Family Foundation E2F 2021 Pilot Award, and the ICTS JIT program, Gabel co-I. In work supported by the M-CM Network and Engelhart Family Foundation, we are characterizing new models of brain overgrowth disorders from individuals with PIK3CA, AKT3, or DNMT3A mutation.
8) Sex differences in autism: “Integrated Analysis of Mechanisms Underlying Sex Epistasis in ASD” Supported by Simons Foundation 2020 SFARI Collaboration on Sex Differences in Autism, Dougherty, Weiss, Turner, Sandin, Yip, co-Is. The goal of this work is to identify non-coding sequence variants that regulate genes in a sex differential manner to contribute to autism susceptibility.
9) Establishing novel stem cell platforms to model developmental disorders in children. In work supported by the Children’s Discovery Institute, and in collaboration with Thor Theunissen and Lila Solnica-Krezel, we are defining how transitions between stem cell states are regulated and using new stem cell models to study pediatric disease.
10) ASO therapy to treat neurodevelopmental disorders involving haploinsufficiency: “Development of ASOs to restore normal MYT1L levels” Supported by the RTW Charitable Foundation, Miller, Dougherty, Djuranovic co-Is. The goal of this work is to develop antisense oligonucleotide (ASO)-based strategies for stabilizing the transcripts encoded by particular genes, and to use this approach to rescue neurodevelopmental disorders involving haploinsufficiency.
11) FBXO31: “FBXO31 patient natural history and mechanisms of disease”, Supported by the Sherman and Joyce Scott Family Foundation Cerebral Palsy Research Fund, Gurnett, A. Johnson co-Is. The goal of this project is to characterize the consequences of pathogenic FBXO31 mutation.