Developmental specification of midbrain dopamine neurons and their connectivity
Dopamine neurons, residing within the ventral midbrain (VM), are essential for the control of voluntary movement, emotion and cognitive function, and are affected in a number of neurological disorders such as Parkinson’s disease, schizophrenia and addiction. Instrumental in improving our knowledge of disease etiology and the development of new therapies will be a greater understanding of how these cells are initially born and wired during embryonic development. While the past 30 years have identified a number of regulators in VM dopamine development, several events remain poorly understood. In this regard the group is interested in identifying novel regulator (including Wnts, chemokines and cell adhesion molecules) in the birth and plasticity of midbrain dopamine neurons.
Cell therapy for brain repair (Parkinson’s disease focused)
Proof of principle for cell replacement therapy in the treatment of Parkinson’s disease was first demonstrated in the clinic using human fetal tissue in the 1980’s. Key limitations in this technology lie in the availability of donor material, graft survival and ensuring appropriate connectivity of the transplanted cells. Research within the group is focused on strategies to identify and select the ideal dopamine neurons, promoting cell survival upon implantation and enhancing integration of transplanted cells into the host tissue. Efforts include the use of neurotrophins such as GDNF to promote survival and plasticity, inhibitors of scar tissue formation (including chondroitinase) and exercise-induced plasticity.
Generation of neuronal subpopulations from pluripotent stem cell sources and their application in disease modelling and brain repair
The Parish laboratory has a keen interest in the use of pluripotent stem cells for brain repair. The team is focused on developing highly standardized protocols for the generation of various neuronal populations from human pluripotent stem cells, with these cells providing valuable tools for disease modeling in the dish, drug screening or transplantation into the injured brain.
A particular interest in the group has been the generation of dopamine neurons, the major cell population that dies in Parkinson’s disease. Using embryonic and induced pluripotent-derived stem cells, the group has successfully generated human dopamine neurons suitable for clinical translation. This has included demonstrating the appropriate identity of the generated cells, their function, as well as the suitability of the protocol for efficient scalability and banking (cryopreservation) of the cells. Most recently we have demonstrated that these stem cell-derived dopamine neurons are capable of alleviating motor symptoms in animal models of Parkinson’s disease. Ongoing work in the team is now focused on developing strategies to purify populations prior to grafting, ensure safety for the use of pluripotent stem cells into the clinic and enhance the integration of these transplanted cells into the host brain.
Parallel stem cell research is also focused on the generation of interneuron, striatal and cortical neuronal populations from mouse and human pluripotent stem cells for in vivo transplantation in diseased models.
Bioengineered scaffolds for brain repair
We adopt an interdisciplinary approach to modelling neural development and repair. In close collaboration with materials engineers we are developing and testing various nanofibrous scaffolds and hydrogels to provide structural support for stem cells and differentiating neurons in vitro as well as provide scaffolding support for transplanted neurons in the injured brain. These scaffolds are designed to closely model the brains extracellular matrix. Furthermore, we are utilizing these scaffolds to provide long-term delivery of functional proteins and viruses – aimed at modulating stem cell proliferation, neuronal differentiation and cell survival.