Despite the importance of Lp(a) as an atherogenic risk factor, a paucity of information, especially from in vivo studies, is available concerning what structural features of apo(a) contribute to Lp(a)'s interactions with the vessel wall and its proatherogenic properties. Nearly all of the proposed and proven activities of apo(a) focus on its high degree of sequence homology with plasminogen and the strong possibility that these shared features and associated interaction/competition with plasminogen determine Lp(a)'s in vivo properties. The focus of this proposal is thus to genetically modify various regions of the apo(a) molecule that are shared with plasminogen emphasizing those with lysine/fibrin biding properties, and then assess in vitro and in vivo the consequences of these changes. A combination of short- and long-term approaches to genetically engineer mice will be performed in order to examine: (1) what apo(a) lysine/fibrin binding sites are functional in Lp(a) and determine whether these sites lay a central role in Lp(a) binding to the vasculature (short-term adenoviral studies): and (2) whether the lysine/fibrin binding properties of apo(a) impact on atherogenesis in mice (long-term transgenic studies). In a separate but mechanistically related series of analyses, the impact of apo(a) on the variety of vascular parameters including atherogenesis will be assessed in plasminogen and fibrinogen knockout mice to explore the interactions between these related molecules. Through analyzing the role of Lp(a) lysine/fibrin binding sites on interactions of Lp(a) with plasminogen, the vasculature and atherogenesis, we are directly examining the major mechanistic pathways which have been proposed to explain the biological properties of Lp(a) in humans. Structural and mechanistic insights into the in vivo activities of Lp(a) to be derived from these studies may help define individuals at risk for atherogenesis on the basis of high-levels of Lp(a) and uncover potential targets for the development of therapies to address this atherosclerosis risk factor.
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