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

乙酰胆碱，通常缩写为ACh，是第一个被确定的神经递质。它参与肌肉的刺激，以及全身神经和大脑细胞之间的交流。在大脑中，乙酰胆碱从参与学习和记忆的细胞中释放出来，涉及记忆丧失的精神健康问题与乙酰胆碱水平的改变直接或间接相关。这些细胞依赖于蛋白质神经生长因子（NGF）的生存和维持。NGF与乙酰胆碱释放细胞表面的TrkA受体结合并激活一种蛋白质。这种NGF-TrkA复合物随后被内化并被运送到细胞体，在那里它可以调节对这些细胞存活至关重要的基因的表达。调控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，我们将使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介导的乙酰胆酸释放细胞的存活。据报道，一氧化氮不仅是一种重要的细胞信使，在某些情况下，一氧化氮还可以作为神经毒素。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一旦进入这些细胞就激活的信号事件，以及在维持这些细胞健康所需的基因表达的调节中。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。绘制出这些细胞中导致基因转录的受体介导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，并可能有助于设计诊断测试或治疗方法，以维持脑细胞的健康或停止细胞损失的各个方面。

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.