The role of thioredoxin system in regulation of synaptic development and neurotransmission in the central nervous system

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During central nervous system development, neurons differentiate from immature cells, subsequently forming synaptic connections and assembling into neuronal circuits. During this differentiation, immature neurons are highly susceptible to factors promoting cellular death, and only fully and appropriately functioning neurons will survive. Although neither cellular nor molecular mechanisms of these processes are yet fully understood, families of biomolecules called neurotrophic factors have been found to play an important role in the regulation of neuronal differentiation, growth and survival. The antioxidant protein thioredoxin can inhibit protein cysteine oxidation and remove hydrogen peroxide from neurons. Therefore thioredoxin is important in the maintaining of the cellular molecular balance - redox homeostasis. Thioredoxin can also bind to the protein apoptosis signal-regulating kinase 1, which promotes cell survival and prevents cell death. In addition, thioredoxin can translocate into the cell nucleus and regulate gene expression. We recently found that thioredoxin protein levels were time-dependently increased during the period of neuronal differentiation, suggesting that thioredoxin may play a role in neuron development and synaptic formation that are important processes for subsequent neuronal functioning. We will determine if thioredoxin regulates neuron differentiation and synaptic formation, neurotrophic factors or neurotransmitter release, and will also identify the specific genes in differentiated neurons that may be targeted by thioredoxin regulation. My research program allows us to study the potential role of thioredoxin in neuronal differentiation, synaptic formation and neurotransmission in brain. The proposed research is original and addresses important questions in the natural sciences. Its outcomes will significantly increase our understanding of the fundamental role played by thioredoxin-regulated signaling in neuronal function. The proposed research in this grant application will bring about a greater understanding of the nature of thioredoxin in physiological regulation of the brain. It will also enable provision of significant training opportunities for students who are interested in working on the science of brain functioning.