Principal Investigator Li-Huei Tsai
The lab has collected human skin fibroblast lines from healthy individuals as well as late onset sporadic AD (LOAD), early onset familiar AD (fAD), ASD, schizophrenia, bipolar disease, and Down syndrome patients and reprogrammed them into induced pluripotent stem cells (iPSCs). We use genome-editing techniques such as Crispr/Cas9 to create isogenic cell lines to facilitate the assessment of phenotypic consequences of disease associated genetic variants. These iPSCs are then differentiated into excitatory neurons, astrocytes, and microglia that can be used for a number of basic and applied research purposes. For example, we can use this system to both examine how specific gene perturbations affect AD-like pathology directly in human neurons and glia, while at the same time screening libraries of drug-like chemicals in a high-throughput fashion to determine potential therapeutic candidates. Increasingly sophisticated culture techniques also allow us to evaluate how disease pathology and genetic variants affect each of the different cell types populating the brain. Using techniques of bioengineering combined with multiphoton deep imaging, optogenetics, and electrophysiology, we can recapitulate and study complex human brain tissue. In these “mini-brain” or organoid cultures, we can examine neuronal and glial activity and examine relevant disease phenotypes such as protein aggregation, neuronal connectivity, and synapse loss. Current efforts are further increasing the complexity of our three-dimensional culture systems to add engineered vasculature that will mimic the blood brain barrier. Ultimately, we hope that these techniques will facilitate drug discovery and testing by allowing us to directly screen engineered human brain organoids for compounds and therapies likely to work in the in vivo human brain.