Macrophage entry into the artery wall is an essential component of atherosclerosis whose complex nature is poorly understood. This grant addresses several different mechanisms by which macrophage entry into the vessel wall may be mediated. First, we have discovered recently that a deficiency of a leukocyte surface glycoprotein called CD43 results in reduced atherosclerosis in LDLR-/- mice. Preliminary data indicated that the reduction in atherosclerosis in the CD43-/- mice may be due to impaired macrophage migration to the lesion, although this is impossible to ascertain given the advanced nature of the lesions. Thus, aim 1 will test the hypothesis that CD43 mediates entry of macrophages to lesion sites. Migration of CD43+/+ or CD43-/- cells into lesions at various developmental stages will be examined. Direct measurement of short-term cell migration will be made using cultured macrophages. In addition, in vitro cell adhesion/migration will be used to identify any ligands that might mediate macrophage movement by binding to the CD43.
Aim 2 will focus on another model of mice in which selectin-mediated leukocyte adhesion is greatly impaired. These mice lack an enzyme called fucosyltransferase VII (Fuc-TVII) that is essential for synthesis of ligands for all 3 (E, L and P) selectins. Fuc-TVII-/- mice will be crossed with the atherosclerosis-prone LDLR-/- mice to determine if macrophages utilize the selectin-ligand interaction to enter the atherosclerotic intima. We will also determine which of the selectin interactions is important for atherogenesis.
The third aim revolves around a protein tyrosine kinase called Fes that is expressed primarily in myeloid cells and is important for myeloid development. Mice deficient in Fes display a striking defect in the ability of their macrophages to adhere. Due to its implications in atherogenesis, Fes deficiency will be studied in relation to lesion development. LDLR-/- mice will be made deficient in Fes to determine if the adherence defect in the Fes deficient macrophages will affect atherosclerotic development. In addition short term in vivo migration study with macrophages from Fes deficient mice will reveal if Fes deficient macrophages may be defective in migrating to atherosclerotic sites. These studies will provide much needed information about macrophage homing to the lesions. Moreover, if these molecules are shown to be essential for macrophage entry into the lesion, specific therapeutic targets can be devised to combat atherosclerosis by inhibiting macrophage migration.
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