FGF SIGNAL TRANSDUCTION IN VASCULAR CELLS

American National Red Cross, Washington DC

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Abstract

DESCRIPTION (Adapted from Investigator's Abstract): Vascular endothelial cell proliferation is associated with the pathogenesis of numerous angiogenic diseases (e.g., cancer, diabetic retinopathy) while smooth muscle cell accumulation occurs during the development of atherosclerosis, transplant associated arteriosclerosis and restenosis after vessel wall injury. It is likely that the fibroblast growth factors (FGF) play an important role in EC and SMC growth control. During the present funding period, the applicant initiated a new research program to identify and characterize FGF-inducible genes. A differential display strategy was successfully used to obtain cDNA clones representing 13 FGF-1 responsive genes expressed in murine NIH 3T3 fibroblasts. In this application, experiments are proposed to characterize in detail one of these genes. This gene (Fn14) is predicted to encode a novel, 14 kDa integral plasma membrane protein. Based upon preliminary data the applicant hypothesizes that Fn14 is involved in growth factor signaling and cell cycle progression. The Specific Aims are: 1) To determine whether the Fn14 protein is expressed at elevated levels in mitogen-stimulated cells and to characterize Fn14 cellular distribution in mouse embryos and tissues using anti-Fn14 antibodies. 2) To determine whether Fn14 is a secretary, membrane-associated or cytosolic protein using several alternative experimental approaches. 3) To determine whether Fn14 plays an important role in cellular proliferation by analyzing the growth properties of cells that express either elevated or reduced levels of the Fn14 protein. It is anticipated that these studies will provide novel information on the mechanism of growth factor signal transduction and may also identify a new therapeutic target for vascular cell antiproliferative therapy.