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

点击翻译按钮获取中文摘要

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.