Context-dependent disease mechanisms of neurodevelopmental disorders

About This Grant

PROJECT SUMMARY/ABSTRACT___________________________________________________________ Neurodevelopmental disorders (NDDs) like autism, intellectual disability, and ADHD are a global health concern. Progress in understanding the causes of NDDs has been slow and treatment options for core symptoms are limited, partially because these brain disorders currently do not have well-defined biological signatures of pathology that can be utilized in experimental neuroscience paradigms or targeted for intervention. There has been considerable recent progress in identifying statistically significant, high-confidence NDD genetic risk variants, including the heterozygous loss of the 16p11.2 chromosomal region (16pdel). Emerging evidence suggests that 16pdel impacts key prenatal neurodevelopmental processes, though the exact disease mechanisms remain elusive. Patients exhibit neuroanatomical features that could potentially be linked to dysregulated response to signal transduction pathway stimulation. Here, we will investigate how 16pdel fetal brain cells respond to key developmental signaling pathway stimulations at the molecular and cellular levels to identify potential dynamic context-dependent disease mechanisms. To address this question, we will leverage a novel in vitro human stem cell-based platform we developed called the "cell village," which enables large-scale, high-throughput analysis of molecular and cellular responses to cell-extrinsic stimuli across diverse neurotypical control and 16pdel patient donor cell lines. This approach minimizes technical variation and allows for systematic exploration of genetic and cellular variability in a controlled uniform environment. By integrating multi-omic datasets, our study aims to uncover the mechanistic links between gene expression, cellular phenotypes, and pathway activation in 16pdel brain cells in a dish. The proposal is structured around three specific aims: First, we will define the nature and dynamics of signaling dysfunction in 16pdels as hypersensitive, hyperresponsive, and/or hyperactivated in response to stimulation. Second, we will decipher the epigenetic mechanisms underlying pathway dysregulation by investigating chromatin accessibility, methylation patterns, and 3D genome organization in first-of-their-kind multi-omic villages. This aim seeks to determine if 16pdel cells are epigenetically primed for aberrant response to signaling pathway stimulation. Third, we will determine the cellular consequences of dysregulated signaling in 16pdels with a particular focus on neurogenesis and morphogenesis mechanisms. By elucidating the molecular mechanisms driving signal transduction pathway dysregulation in 16pdel fetal brain cells, as well as the impact on cellular functions critical for proper neurodevelopment, this research could illuminate the fundamental neurobiology of a high-confidence genetic risk factor associated with complex NDDs and nominate future targets for intervention, thus improving outcomes for patients and their families.