DISTINCT HUMAN MACROPHAGE RECEPTOR FOR ABNORMAL VLDL

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DESCRIPTION: (Adapted from the Investigator's abstract): Macrophage-derived foam cells accumulate in atherosclerotic lesions and throughout the body in some forms of hypertriglyceridemia (HTG). Uptake of abnormal triglyceride-rich lipoproteins (abTGRLP) by a macrophage receptor(R) distinct from the LDL R and the acetyl LDL R that the investigators recently described in murine macrophages and human monocyte-macrophages may be responsible for foam cell formation in HTG humans. Moreover, this R also binds oxidized LDL with high affinity, suggesting that this pathway may be important in foam cell formation in hypercholesterolemia as well as in HTG. The goals of the proposed work are (1) to isolate and characterize the human monocyte-macrophage receptor for abnormal TGRLP and (2) to identify the binding determinants present in abTGRLP that are absent or masked in TGRLP from normal subjects and to determine if lowering plasma TG levels in HTG subjects normalizes the TGRLP. The human monocytic line THP-1 will be used as a source for purification of plasma membrane binding proteins identified as likely receptor candidates for partial microsequencing and production of antibodies against the receptor. Molecular biological approaches will identify receptor complementary DNA clones to elucidate receptor primary structure and to characterize cellular mRNA. Competitive and direct cell binding and ligand blotting studies with native and modified VLDL, model VLDL, and mapped monoclonal antibodies against apoB will identify binding determinants. These studies should provide basic cellular and molecular mechanisms pertinent to foam cell formation in humans.