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

在中枢神经系统发育期间，神经元从未成熟细胞分化，随后形成突触连接并组装成神经元回路。在这种分化过程中，未成熟的神经元对促进细胞死亡的因素非常敏感，只有功能完全和适当的神经元才能存活。虽然这些过程的细胞或分子机制尚未完全理解，但已发现称为神经营养因子的生物分子家族在调节神经元分化，生长和存活中起重要作用。 抗氧化蛋白硫氧还蛋白可以抑制蛋白质半胱氨酸氧化，清除神经元中的过氧化氢。因此，硫氧还蛋白在维持细胞分子平衡-氧化还原稳态中是重要的。硫氧还蛋白还可以结合蛋白质凋亡信号调节激酶1，其促进细胞存活并防止细胞死亡。此外，硫氧还蛋白还可以转位到细胞核中，调节基因表达。我们最近发现，硫氧还蛋白蛋白的蛋白水平在神经元分化期间呈时间依赖性增加，这表明硫氧还蛋白可能在神经元发育和突触形成中发挥作用，这是后续神经元功能的重要过程。我们将确定硫氧还蛋白是否调节神经元分化和突触形成，神经营养因子或神经递质释放，并确定在分化的神经元中可能被硫氧还蛋白调节靶向的特定基因。 我的研究项目使我们能够研究硫氧还蛋白在脑神经元分化、突触形成和神经传递中的潜在作用。拟议的研究是原创性的，并解决了自然科学中的重要问题。它的结果将显着增加我们的硫氧还蛋白调节信号在神经元功能中发挥的基本作用的理解。这项拨款申请中的拟议研究将使人们更好地了解硫氧还蛋白在大脑生理调节中的性质。它还将为有兴趣从事大脑功能科学工作的学生提供重要的培训机会。

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.