| Summary: | 碩士 === 國立清華大學 === 分子醫學研究所 === 97 === During development of vertebrate nervous system, neurons compete for limited target-derived trophic factors for survival. Insufficient neurotrophic support renders cells undergoing programmed cell death. Although cell death is a normal process during neuronal development, abnormal cell death of matured neurons and progressive loss of structure or function results in neurodegeneration such as Alzheimer’s disease and Parkinson’s disease. The adaptor protein SH2B1β is a signaling molecule that participates in various signaling pathway including nerve growth factor (NGF) and fibroblast growth factor (FGF) signaling. SH2B1β also enhances NGF- as well as FGF1-induced neurite outgrowth in PC12 cell, a well-established neuronal model that can be differentiated into sympathetic-like neurons upon NGF challenge. Moreover, our recent results suggest that SH2B1β could reduce oxidative stress-induced cell death. Oxidative stress has been linked to the neuronal cell death, which is associated with various neurodegenerative conditions. These results lead us to hypothesize that SH2B1β may play a role in neuronal degeneration and/or regeneration. In this study, I have shown that SH2B1β reduces neuronal degeneration during NGF deprivation and enhances regeneration after nerve injury. In addition, SH2B1β regulates the pro-inflammatory cytokines-induced signaling. To understand the mechanisms by which SH2B1β exerts its effect, we use wound healing assay as an injury model to investigate how SH2B1�� enhances neuronal regeneration. I have found that SH2B1��-overexpressing cells express higher level of growth-associated protein-43 (GAP-43), that may promote regeneration. In addition, down-regulation of STAT3, NCAM-L1, and N-cadherin might affect cell motility which leads cells migrate to the wounded area to promote regeneration. Taken together, SH2B1β may utilize multiple mechanisms to promote regeneration.
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