Role of NO in NGF trafficking, kinase phosphorylation and transcription factor activation in cholinergic neurons

NO 在胆碱能神经元 NGF 运输、激酶磷酸化和转录因子激活中的作用

• 批准号: 262000-2008
• 负责人: Kalisch, Bettina
• 金额: $ 1.97万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=426900
• 关键词: Role; NO; NGF; trafficking; kinase

Acetylcholine, often abbreviated as ACh, was the first neurotransmitter to be identified. It is involved in the stimulation of muscle as well as communication in nerves through out the body and between cells in the brain. In the brain, ACh is released from cells that are involved in learning and memory and mental health issues that involve memory loss relate directly or indirectly to alterations in the levels of ACh. These cells depend on the protein nerve growth factor (NGF) for their survival and maintenance. NGF binds to and activates a protein, known as the TrkA receptor on the surface of the ACh-releasing cells. This NGF-TrkA complex then becomes internalized and is transported to the cell body where it can regulate the expression of genes that are critical for the survival of these cells. The mechanisms that regulate the expression of these genes are not completely understood, however it is clear that the binding of NGF to TrkA is necessary. In the proposed studies, we will use cellular and molecular biology to gain a better understanding of how NGF enhances gene expression in these cells. Recently, the molecule nitric oxide has been implicated in these actions of NGF so our specific aim is to understand how NO contributes to the NGF-mediated survival of ACh-releasing cells. Not only has NO has been reported to act as an important cellular messenger, in some situations NO acts as a neurotoxin. In order to elucidate the these mechanisms, we propose to investigate the role of NO in the uptake of NGF into ACh-releasing cells, the signalling events that NGF-TrkA activates once inside these cells and in the modulation of the expression of genes necessary for maintaining the health of these cells. Understanding how NO influences gene expression could be useful in identifying the protective versus toxic effects of NO in the brain. Mapping out the receptor-mediated elements that lead to gene transcription in these cells will contribute to a broader understanding of how activation of multiple signalling pathways can lead to specific cellular responses in a number of biological processes and could be useful in the design of diagnostic tests or therapies that would maintain the health of brain cells or halt aspects of cell loss.

乙酰胆碱，通常缩写为 ACh，是第一个被识别的神经递质。它参与肌肉的刺激以及整个身体和大脑细胞之间的神经通讯。在大脑中，乙酰胆碱是从参与学习和记忆的细胞中释放出来的，而涉及记忆丧失的心理健康问题则与乙酰胆碱水平的变化直接或间接相关。这些细胞的生存和维持依赖于蛋白质神经生长因子（NGF）。 NGF 结合并激活一种蛋白质，即乙酰胆碱释放细胞表面的 TrkA 受体。然后，这种 NGF-TrkA 复合物被内化并被转运到细胞体，在那里它可以调节对这些细胞的生存至关重要的基因的表达。调节这些基因表达的机制尚不完全清楚，但很明显 NGF 与 TrkA 的结合是必要的。在拟议的研究中，我们将利用细胞和分子生物学来更好地了解 NGF 如何增强这些细胞中的基因表达。最近，一氧化氮分子与 NGF 的这些作用有关，因此我们的具体目标是了解 NO 如何促进 NGF 介导的乙酰胆碱释放细胞的存活。据报道，NO 不仅充当重要的细胞信使，在某些情况下，NO 还充当神经毒素。 为了阐明这些机制，我们建议研究 NO 在 NGF 摄取到 ACh 释放细胞中的作用、NGF-TrkA 在这些细胞内激活的信号事件以及在调节维持这些细胞健康所需的基因表达中的作用。了解 NO 如何影响基因表达可能有助于确定 NO 在大脑中的保护作用和毒性作用。 找出导致这些细胞中基因转录的受体介导的元件，将有助于更广泛地了解多种信号通路的激活如何在许多生物过程中导致特定的细胞反应，并可用于设计维持脑细胞健康或阻止细胞损失的诊断测试或疗法。