The long range goal of this proposal is to increase our understanding of the mechanisms involved in the pathogenesis of atherosclerosis. Atherosclerotic lesions contain elevated levels of macrophage-colony stimulating factor (M-CSF or CSF-1). The presence of M-CSF in the normal artery correlates with an increase in the arterial lesion suggesting that M-CSF may contribute significantly to the initiation and/or progression of atherosclerosis by affecting monocyte-mac ophage function and survival in the artery wall. Our previous studies indicate that induced expression of M-CSF at focal sites within the artery wall may be one link among the injurious effects of various atherogenic agents. The overall objectives of these studies are to extend our work using combined biochemical and molecular genetic approaches to investigate the mechanisms involved in the vascular injury-induced expression of M-CSF, and to examine the aspects of the mechanisms through which M-CSF participates in the pathogenesis of atherosclerosis. The specific aims include 1) to investigate the effects of M-CSF on its own expression and the expression of its receptor and several other cytokines and growth factors using cultured human artery wall cells, 2) to use in vitro mutagenesis and transient expression assays to identify the cis-acting DNA elements involved in the vascular injury-induced or autoinduced upregulation of the human M-CSF gene, 3) to test the M-CSF cis-acting DNA elements for binding to specific nuclear proteins and identify trans- acting factors that participate in the vascular injury-mediated transcriptional activation, 4) to use mouse model of arterial injury to examine the induced expression of M-CSF and its receptor in vivo, and 5) to investigate the effects of M-CSF ont he growth of arterial lesion- associated cells in vivo using osteopetrotic (op/op) mice that totally lack M-CSF and apolipoprotein E (apoE)-deficient mice that exhibit accelerated atherosclerosis. The proposed experiments will provide important information that will enhance our understanding of the role of M-CSF in the pathogenesis of atherosclerosis, and may prove valuable in developing ways to control the disease.

R29HL051980

1994-12-01

2000-11-30