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过程中，神经元从未成熟细胞分化而来，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，未成熟神经元非常容易受到促进细胞死亡的因素的影响，只有完全和适当功能的神经元才能存活。尽管这些过程的细胞和分子机制尚不完全清楚，但被称为神经营养因子的生物分子家族已被发现在神经元分化、生长和存活的调节中发挥重要作用。 抗氧化蛋白质硫氧还蛋白能抑制蛋白质半胱氨酸的氧化，并能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-氧化还原动态平衡中起着重要作用。硫氧还蛋白还可以与调节细胞凋亡信号的蛋白激酶1结合，促进细胞存活，防止细胞死亡。此外，硫氧还蛋白还可以移位到细胞核内，调节基因表达。我们最近发现，在神经元分化过程中，硫氧还蛋白水平呈时间依赖性增加，提示硫氧还蛋白可能在神经元发育和突触形成过程中发挥作用，而这两个过程是随后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，还将确定分化神经元中可能成为硫氧还蛋白调控靶点的特定基因。 我的研究项目使我们能够研究硫氧还蛋白在大脑中神经元分化、突触形成和神经传递中的潜在作用。这项拟议的研究具有原创性，涉及自然科学中的重要问题。它的结果将显著增加我们对硫氧还蛋白调节的信号在神经元功能中所起的基础作用的理解。这项拨款申请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。它还将为对大脑功能科学感兴趣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.