Modeling of GATAD2B-associated neurodevelopmental disorder and NuRDopathies: Investigation of cellular & molecular anomalies altering neurodevelopment
Grant Award Details
Grant Type:
Grant Number:
DISC0-15774
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Cell Line Generation:
Award Value:
$1,318,441
Status:
Active
Grant Application Details
Application Title:
Modeling of GATAD2B-associated neurodevelopmental disorder and NuRDopathies: Investigation of cellular & molecular anomalies altering neurodevelopment
Public Abstract:
Research Objective
Human and animal models of NuRD-deficiency will identify NuRD-subtype function in context of neurogenesis.
Multi-omic studies will identify/quantify molecular and cellular changes in NuRD-deficiency.
Impact
NuRD-deficiency causes several neurodevelopmental disorders (NDDs), our work will identify and quantify cellular and molecular changes in human and mouse models of corticogenesis with NuRD deficiency.
Major Proposed Activities
Human and animal models of NuRD-deficiency will identify NuRD-subtype function in context of neurogenesis.
Multi-omic studies will identify/quantify molecular and cellular changes in NuRD-deficiency.
Impact
NuRD-deficiency causes several neurodevelopmental disorders (NDDs), our work will identify and quantify cellular and molecular changes in human and mouse models of corticogenesis with NuRD deficiency.
Major Proposed Activities
- We will generate GAND-IPSCs with inducible expression of HA-GATAD2B to correct these cells' phenotypes seen in NPC growth assays and in the spatial and temporal expression of cortical laminar markers.
- We will generate GAND-IPSCs with inducible expression of HA-GATAD2A to see if GATAD2B's paralog can function to correct the cellular phenotypes seen in NPC growth and cortical laminar marker assays.
- GAND-IPSCs with inducible knockdown of GATAD2A will determine if repression of GATAD2A can function to correct the cellular phenotypes seen in NPC growth and cortical laminar marker expression assays.
- GAND-IPSCs will be used to generate cerebral organoids and using immunohistochemistry will determine if NPC and cortical neuron subtypes are generated and coexpress cortical laminar markers.
- GAND-IPSCs will be differentiated into cerebral organoids (excitatory/inhibitory) and undergo snRNA-seq/snATAC-seq to identify dysregulated genetic pathways within NPCs/neurons with NuRD-deficiency.
- Gatad2b-deficient mouse cortices will undergo snRNA-seq/ATAC-seq to identify dysregulated genetic pathways and altered cellular subpopulations in NPCs/neurons to inform/confirm human IPSC data.
Statement of Benefit to California:
Neurodevelopmental disorders (NDDs) affect >3% of the world’s population. Understanding the mechanisms of NDDs is imperative for developing potential therapies to assist families. The focus of our work is the use of patient-derived IPSCs and mouse models to study the epigenetic dysregulation found in NuRD-deficiency and other NDDs. We hope to identify abnormalities in NuRD-deficiency that can be applied to many NDDs, while also fulfilling CIRM’S goal of understanding brain disorders.