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Determining how cholesterol-rich Lp(a) causes heart disease

Institution: J. David Gladstone Institutes
Investigator(s): Thomas Innerarity, Ph.D. Robert Pitas, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0018 Award: $797,092
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Coronary heart disease is the main cause of death for both men and women in western countries. Cigarette smoking is associated with an increased incidence of premature atherosclerosis, which causes myocardial infarctions. Another important risk factor for developing coronary artery disease is elevated blood levels of the unusual fat-transporting protein Lp(a). Together, elevated blood levels of Lp(a) and cigarette smoking greatly exacerbate the risk of coronary heart disease. In addition, at least one study suggests that cigarette smoking specifically alters Lp(a) concentrations in the blood. The molecular mechanism of how high levels of Lp(a) causes increased atherosclerosis is still unclear. In this proposal we will explore the hypothesis that Lp(a) becomes trapped in the walls of blood vessels by binding to specific proteins in the artery wall known as the proteoglycans and fibrin. Since Lp(a) is a combination of Low Density Lipoprotein (LDL, the "bad" cholesterol-transporting plasma protein) and apo(a) (another plasma protein) we will attempt to generate Lp(a) that binds poorly to the components of arterial walls.

Using advanced molecular biology techniques we have been able to genetically engineer LDL in such a way that it does not bind to proteoglycans. In transgenic mice this LDL has shown little ability to cause atherosclerosis. Similarly, one of our collaborators has engineered apo(a) in such a way it does not bind fibrin (another component of the artery wall). When expressed in transgenic mice this modified apo(a) is poorly retained in arterial walls. These genetically modified Lp(a) will be expressed in transgenic mice to determine if they are less atherogenic than normal Lp(a). If the genetically altered Lp(a) are less atherogenic we will know that their binding to proteoglycans and/or fibrin are an important step in initiating atherosclerosis in mice and most likely in man as well. In summary, these studies should help clarify how Lp(a) induces atherosclerosis. Moreover, if these genetic studies establish that the inhibition Lp(a) binding to proteoglycans and/or to other key blood proteins is anti-atherogenic, then the therapeutic potential of using small molecules to inhibit Lp(a) binding becomes a new viable approach for inhibiting or preventing atherosclerosis in humans.

Phylogenetic analysis of the Apolipoprotein B mRNA editing region: evidence for a secondary structure between the Mooring-sequence and the 3' efficiency element
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Hersberger M, Patarroyo-White S, Arnold K, Innerarity TL ART
Yr: 1999 Vol: 274 Nbr: Abs: Pg: 34590-34597