Barrett, Lindy Elise PHD

This project proposes to develop novel human induced pluripotent stem cell (iPSC) tools to study NSD1 haploinsufficiency and to generate pilot data on NSD1 molecular function in human neurons. These tools and datasets will be used to accelerate our understanding of how NSD1 haploinsufficiency drives the neurodevelopmental phenotypes observed in Sotos syndrome.

This project uses human induced pluripotent stem cell (iPSC) models to investigate the novel hypothesis that dysregulation of histone modifications in Down syndrome (DS) drives downstream molecular and cellular phenotypes. In addition to elucidating fundamental mechanisms of epigenetic re-wiring in DS, this project will explore a set of key unanswered questions in the field, and test the utility of epigenetic modifiers for normalizing histone phenotypes which has the exiting potential to illuminate new therapeutic targets.

The goal of this proposal is to elucidate fundamental molecular mechanisms of the RNA binding protein FMRP in relevant human cell types. Our preliminary data show that FMRP binds pre-mRNA targets in human embryonic stem cells and excitatory cortical neurons, and we will now test as series of hypotheses regarding FMRP’s role in RNA processing. As loss of FMRP is causative for Fragile X syndrome, these data have important implications for human disease biology.

This project investigates epigenetic dysregulation in Down Syndrome using human induced pluripotent stem cell (iPSC) models. In addition to uncovering basic mechanisms of Down syndrome that overlap with other neurodevelopmental disorders, epigenetic modifiers are an active area of therapeutic development and we speculate these data could uncover novel, clinically relevant targets for Down syndrome patients.