Discovery of new treatments for brain development disorders linked to epigenetic regulatory genes

Summary Discovery of new treatments for brain development disorders linked to epigenetic regulatory genes

Project Details

The cerebral cortex -  the outer layer of the brain - is highly expanded in humans compared to other mammals, and it is this unique human characteristic which is thought to account for our species increased intellectual capacity.  Impaired cognition, as observed in people with intellectual disabilities, is often associated with defects during brain development.

Due to advances in human genetic sequencing, a large number of developmental disorders associated with intellectual disabilities have being linked to genetic mutations in specific genes.  Interestingly, a large number of these genes are involved in epigenetic regulation - a cellular processes which regulates which genes are expressed or silenced through reversible modification of histones or DNA.

Cortical development is a highly complex process which requires tight and timely control over transcriptional programmes orchestrating expression and silencing of a multitude of genes which govern various cellular processes including proliferation, migration and neuronal differentiation. Therefore misfunction of epigenetic genes which regulate these transcriptional programmes result in failures in one or more of these cellular processes during cortical development and lead to long-term intellectual disability.

The broad aims of this project are to: 1. Model human cortical development in vitro using human embryonic stem cell (hESC) and induced pluripotent stem cells (iPSC) derived from intellectually disabled patients harbouring deleterious mutations 2. Identify gene-dependent deficits during cortical development 3. Run a small-scale drug screen for treatment of these genetic disorders.

Successful candidates will generate a battery of genetically modified hESCs using CRISPR-Cas9 mediated gene disruption, perform in vitro cortical differentiation, conduct neuronal phenotype analysis using live cell confocal imaging of genetically encoded fluorescent reporters, assess electrophysiological properties of neurons using MEA assays, conduct biochemical analyses of epigenetic markers along with performing basic molecular biology techniques such as cloning, genotyping PCR, western blot and immunocytochemistry.