Human dermal fibroblasts constitute a suitable system to study growth regulation. These cells alternate between states of proliferation and quiescence under the control of growth factors, hormones, and extracellular matrix proteins elaborated by the fibroblasts. Complex interconnected pathways transmit these extracellular signals to growth processes in the cell. The objective of this proposal is to elucidate this signal transduction network. A mutant cell type derived from benign dermal tumors, keloids, will be used to help unravel the regulatory network. The keloid mutation modifies growth regulation by phorbol esters, prostaglandins and transforming growth factor beta, substances that may act as positive or negative effectors of growth. Signal transduction pathways of these regulators are incompletely understood; however, several important intracellular messengers have been implicated. Methods to be used include measurements of prostaglandin synthesis, prostaglandin receptors, and intracellular concentrations of cyclic AMP, Ca2+ and inositol phosphates after exposure of normal and keloid cells to effectors that differentially regulate DNA synthesis in these cell types. The temporal pattern of signal transduction intermediates in normal and keloid cells should reveal the signalling pathways of these regulators and may clarify the complex interactions that coordinate and modulate growth-associated activities. Three minority graduate students will participate in the research with three researchers in the Microbiology Department at Meharry Medical College.
