This is an application for competitive renewal of a grant to study control of expression of the atherogenic lipoprotein, lipoprotein(a) [Lp(a)]. Plasma levels of Lp(a) correlate generally with propensity for vascular diseases (myocardial infarction, re-stenosis, and stroke). The applicant proposes to utilize both in vitro and in vivo (transgenic model) approaches to delineate how the 1000-fold variation in plasma levels of Lp(a) in humans, which appears to be at least partially genetically determined, is accomplished. The applicant will examine the mechanism by which sex hormones and dietary fats may influence expression of Lp(a), principally by studying their interactions with polymorphic flanking sequences in the human apo(a) gene. The proposal consists of three Specific Aims. First, having already isolated 1400 base pairs of proximal promoter region, the investigators will clone additional upstream sequences in order to identify the hormone and cytokine response elements. Second, control of apo(a) expression will be assessed in vivo by constructing transgenic mice that harbor apo(a) constructs bearing or lacking specific control elements or regions. Third, the applicant will employ transgenic mouse models to test therapeutic modalities, such as estrogen and tamoxifen, which are designed to suppress expression of apo(a).
