The proposed Program consists of four projects and four cores all aimed at studying the structural, molecular and functional basis of the heterogeneity of lipoprotein(a) or Lp(a), a lipoprotein particle which has been associated with an increased prevalence of atherosclerotic cardiovascular disease. Project 1 will be directed at defining the effect of apo(a) glycation and size polymorphism on the structural and immunological properties of various Lp(a) species and at complementing the studies with the analysis of individual apo(a) kringles expressed in pro- and eukaryotic cells. Project 2 will deal with the characterization of the intravascular remodeling events involving both cholesteryl ester-and triglyceride-rich Lp(a) particles with a particular emphasis on understanding their metabolic and functional significance. Project 3 will examine the various steps of the assembly and secretion of Lp(a) particles in transfected cells and in primary human hepatocyte cultures as well as the factors that regulate these processes. Project 4 will be concerned with the study of the functional heterogeneity of Lp(a) particles having well defined apo(a) genotypes and phenotypes as well as genetically determined apo(a) mutants as assessed by binding to lysine- and proline- Sepharose columns, cellular and extracellular matrices and U937 macrophages. The activities of the four projects will rely on three scientific cores: Lp(a) analytical, Lp(a) preparative and cell culture as well as on an administrative core. The results of these multidisciplinary studies are expected to shed more light on the structure and biology of Lp(a), and also on its role as a cardiovascular pathogen.
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