The focus of our research in the lab is on how the brain develops and ages, and how changes to this process can cause conditions such as Down Syndrome and dementia.
Making a brain depends on producing all of the different types of nerve cells in the correct places and at the appropriate times before wiring those nerve cells together to make functional circuits.
Growing human brain cells in a dish enables us to study them using techniques which are not possible to perform in vivo. Differentiating cortical nerve cells from induced pluripotent stem cells enables us to study patient-specific neurons for a range of conditions.
We study how neural stem and progenitor cells build the executive centre of the brain, the cortex. The cortex is the part of the front of the brain that mammals, including humans, use to perceive physical sensations, sound and vision and where thoughts are generated and movement initiated. The consequences of changes to important genes or of mis-wiring in the cortex are neurological diseases, disability, and neuro-degeneration; including epilepsy and autism, major learning disabilities and dementia.
An understanding of how the cortex is built normally is essential for understanding these disorders, as is our research into what causes the system to break down.
The cerebral cortex makes up three quarters of the human brain, and is responsible for cognition and perception. Understanding the biology of cortical neural stem cells is essential for understanding human evolution, the pathogenesis of human neurodeveopmental disorders and the rational design of neural repair strategies in adults.
In the group, we have developed methods for directing differentiation of human pluripotent stem cells to cortical neurons, via a cortical stem cell stage. Human stem cell-derived cortical neurons form functional networks of excitatory synapses in culture.
This system recapitulates in vivo development to generate all classes of cortical projection neurons in a fixed temporal order, which enables functional studies of human cerebral cortex development and to generate individual-specific models of cortical disorders ex vivo for disease modeling and therapeutic research.
Our initial focus has been on dementia, where we have used stem cells from people with Down syndrome and from patients with familial AD to create cell culture models of Alzheimer’s pathogenesis in cortical neurons. We are using those models to study cellular processes of the disease and the efficacy of current therapeutic strategies.
Our three primary research questions are:
• What are the principle mechanisms causing neurodegeneration in Alzheimers?
• How does disease-associated genetic variation within populations affect development and pathology of cortical neurons?
• What can we do to modulate the disease process?