• Lanford, Robert E (PI)

    Project: Research project

    Project Details


    Coronary heart disease (CHD) is responsible for almost half of all deaths
    in western countries. A number of environmental factors have been
    identified as increasing the risk of this disease, i.e., smoking, high
    fat diet, and lack of exercise. However, a strong genetic influence
    exists as well. The plasma levels of lipoproteins(s), Lp(a), are highly
    heritable, and increased Lp(a) levels are a strong, independent risk
    factor atherosclerosis, the major cause of CHD. Lp(a) consist of low
    density lipoprotein (LDL) in which apoB is disulfide-linked to an
    additional high molecular weight glycoprotein, apo(a). Apo(a) is
    synthesized by the liver and exists as a number of genetically determined
    isoforms that vary in size from 400 to greater than 800 kDa. The plasma
    levels of Lp(a) vary from less than 1 to greater than 100 mg/dl, and
    there is a tendency for an inverse correlation between isoform size and
    plasma concentration. Despite its clinical significance, virtually
    nothing is known about factors which regulate rates of Lp(a) production
    and removal from the circulation. A great need therefore exists for an
    in vitro system to analyze the factors regulating the synthesis and
    secretion of this highly atherogenic lipoprotein. Baboons show similar
    characteristics to humans in terms of plasma levels of Lp(a) and apo(a)
    isoform sizes. We have developed a serum-free medium that maintains
    highly differentiated baboon hepatocytes in culture for extended times,
    and, recently, we have demonstrated the utility of this system for
    analyzing the morphogenesis of Lp(a). The first specific aim of this
    proposal is to examine the synthesis of apo(a) in hepatocytes obtained
    from genetically selected baboons expressing high and low levels of
    plasma Lp(a). The influence of allelic variation will be examined for
    the level of apo(a) mRNA transcription, the rate of apo(a) polypeptide
    synthesis, the kinetics of intracellular maturation of apo(a), and the
    level of apo(a) intracellular degradation. The second specific aim is
    to conduct an in depth analysis of the intracellular maturation of apo(a)
    including protein folding, association with chaperones in the endoplasmic
    reticulum, and the association of apo(a) with proteins in the trans-
    Golgi. The third specific aim is to examine the nature of and
    requirements for the interaction between apo(a) and apoB to form Lp(a).
    In the fourth specific aim, compounds of potential therapeutic benefit
    in lowering Lp(a) concentrations will be examined in vitro for their
    mechanism of action. The final specific aim is to develop immortalized
    hepatocyte cell lines that are suitable for analysis of apo(a)
    Effective start/end date8/15/937/31/99


    • National Institutes of Health: $278,591.00


    • Medicine(all)


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