These studies address issues related to the general problem of post-transcriptional interfaces between receptor-mediated signal transduction and mechanisms that control gene expression, focusing specifically on gene regulation within VSMC by receptors natively expressed on their cell surface. Many different factors that stimulate cell surface receptors have been implicated in causing atherosclerosis and hypertension. The pleiotropic sensitivity of vascular cells to so many factors implies that inhibition of any single receptor would be less effective at preventing progression of vascular disease compared to an inhibitor of a final common pathway. Receptor-mediated induction of IL-6 mRNA in VSMC will be used as a model problem of signaling integration in VSMC, and will focus specifically upon the hypothesis that regulated post-transcriptional mechanisms contribute to patterns of IL-6 mRNA induction. This will be accomplished largely by using a novel and powerful approach in which recombinant IL-6 mRNA's will be transcribed from tetracycline-suppressible promoters within intact cultured VSMC. This approach allows selective control of transcription of the mRNA, and the measurement of how receptor-mediated signaling modulates mRNA decay. The proposed studies will 1) determine which cell surface receptors and what signaling pathways modulate IL-6 mRNA stability in VSMC; 2) identify the structural regulatory elements in the IL-6 mRNA that mediate signaling regulated-stabilization; and 3) directly measure the degree to which IL-6 mRNA induction involves coordinated activation of transcriptional and post-transcriptional regulatory processes.
