| dc.description.abstract | Systems biology methodologies have the advantages of supplementing the conventional mode of study by facilitating the understanding of biological pathways and mechanisms in terms of their dynamic system behavior on different levels of organization rather than the static interaction among the individual molecular and cellular elements. In this study, I set up an in vivo and in vitro models to study the signal transduction pathways in each system. In the in vivo model, I investigated neuronal sensitivity to a noxious stimulus in a rat model of neonatal hind-paw peripheral inflammation and assessed changes in pain behavior at the physiological and molecular levels after peripheral reinflammation in adulthood. After reinflammation, an increase in the expression of the prodynorphin (proDYN) gene was noted in the spinal cord ipsilateral to the afferents of the neonatally treated hind paw. The involvement of the activation of extracellular signal-regulated kinases (ERK) in peripheral inflammatory pain hypersensitivity was evident by the increase in phospho-ERK (pERK) activity after reinflammation. This indicates that peripheral inflammation in neonates can alter the pain processing pathway through the activation of the MAPK/ERK pathway through the expression of the dynorphin. Due to the complexity of the animal models, signal transduction mechanisms are also examined in the PC12 cell culture systems. In this in vitro model, I investigated through the molecular biology paradigm, as well as high throughput experiments and system biology analysis, the genes and pathways associated with Nerve Growth Factor (NGF) induced neuronal differentiation, as PC12 cells were also known to produce dynorphin after NGF stimulation. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database was used to match the data from microarray experiments to biologic networks in the KEGG database. Cross-matching to the KEGG gene database resulted in 830 genes. Among these, I identified 395 genes with their expressions significantly altered compared to the baseline expressions. I also identified 191 involved biologic pathways in the KEGG database. The most active pathways include the mitogen-activated protein kinase (MAPK) pathway, axonal guidance pathway, the Wnt pathway, and the neurotrophin pathway. Thus, these studies showed that in both the NGF induced neuronal differentiation and inflammation induced pain modulation, multiple pathways were activated including, most notably, the MAPK/ERK pathway. As in the in vitro PC12 model system, NGF may also play a role in the inflammation induced pain modulation in the in vivo animal model system. | en_US |