MAPKs ERK, JNK and P38 in inflammatory and oxidative stress signaling investigated in human lung and skin fibroblasts.

摘要

This dissertation addresses three fundamental questions about alterations in signal transduction mechanisms relevant to the human biology of aging and neurodegenerative disease: (1) How does a G-protein coupled receptor (GPCR) modulate its affinity for its ligand to adapt cellular responses to environmental conditions such as stress signals? Receptor phosphorylation. (2) What is the relevance of the receptor phosphorylation? Altered signal transduction for stress response. (3) What are the downstream consequences of this stress-induced receptor modulation? Differential MAPK activation profiles.;Our exploration of G-protein coupled receptor (GPCR) signaling involves the mechanistic understanding of pathways governed by the GPCR for the inflammatory neuropeptide Bradykinin (BK). The B2R subtype participates in signaling for cellular proliferation, wound healing, tissue repair, vasodialation and cardiac homeostasis and its dysfunction has been linked to asthma, artherosclerosis, hypertension and Alzheimer's disease (AD).;To our advantage, we utilize peripheral tissue cellular model systems such as human lung and skin fibroblasts to investigate endogenously expressed proteins undergoing changes in expression or activation in an aging model setting or proteins suspected to go awry in a disease model setting. We had previously uncovered a novel phosphorylation modulation of B2R giving rise to BK-induced B2R isoforms enhanced in aging and AD cellular models. I have currently defined the nature of the receptor phosphorylation as well as participants of the B2R modulatory kinase network involving EGFR, Src and PKC.;Stimulus specific mediation of GPCR signal transduction culminating in MAPK activation has been well-substantiated in the AD field as cascades involved in sensing, mediating and responding to stress. Inflammatory and oxidative stresses, both being early events in AD development, are two additional focal points of my dissertation research investigations. BK-induced inflammatory stress revealed differential MAPK activation profiles dependent on the severity of familial AD genetic mutation. Collectively, the MAPKs appear to be a key readout for GPCR signal transduction pathways in response to external stress signals. The elucidation of GPCR signaling details and points of diversion or conversion is conceptually important for future drug target intervention in GPCR disorders like AD.