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LDL pathophysiology and lipoprotein structure

Institution: Children's Hospital Oakland Research Institute
Investigator(s): Robert Ryan, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12RT-0014 Award: $527,245
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Mainstream and environmental tobacco smoke exposure represent significant risk factors for cardiovascular disease in men and women. The relationship between smoking and cardiovascular disease results from multiple mechanisms that interact to contribute to vascular injury and atherosclerosis lesion development. We are only beginning to understand how smoking contributes to the initiation and progression of cardiovascular disease. One area of intense interest is the effect of tobacco smoke on plasma lipoprotein particles. These particles, which normally function in transport of insoluble lipids through the bloodstream, have been recognized as a target for tobacco combustion-related oxidative damage. A specific type of lipoprotein, termed low density lipoprotein, is adversely affected by oxidation, being converted to a species that accelerates the progression of atherosclerosis lesion development. From knowledge that oxidized low density lipoproteins accumulate at the site of atherosclerosis lesion development, it can be concluded that susceptibility of these particles to oxidative modification caused by tobacco smoke exposure may constitute a contributing factor to disease progression.

The goal of our research is to understand the molecular basis whereby a protein component of circulating lipoproteins facilitates their removal from the circulation and hence, decreases the amount of low density lipoprotein available for oxidative modification. Apolipoprotein E associates with the surface of plasma lipoprotein particles and mediates interaction with cell surface receptor molecules. From knowledge of the structure of apolipoprotein E and the fact that this protein can alter its conformation in such a way that it is, or is not, recognized by lipoprotein receptors forms the basis for our research endeavor. We hypothesize that increasing the proportion of apolipoprotein E that adopts a receptor-active state will result in a decrease in plasma low density lipoprotein concentration and, hence, lowered susceptibility to tobacco smoke related oxidation events and pathological lipoprotein metabolism. We will conduct studies designed to ascertain the structural elements in apolipoprotein E that are responsible for initiating interaction with the surface of lipoproteins. In addition we will evaluate the effect of specific structural and biochemical factors on the ability of apolipoprotein E to adopt a conformation that is recognized by lipoprotein receptors. In a third phase of this project we will establish conditions for discerning alternate conformational states of apolipoprotein E on the surface of plasma lipoproteins. These studies will increase our knowledge of how apolipoprotein E functions to regulate lipoprotein levels in plasma and provide the basis for new strategies to decrease tobacco smoke exposure related lipoprotein damage that promotes and accelerates the pathology of cardiovascular disease.
Publications

Replacement of helix1' enhances the lipid binding activity of apo E3 N-terminal domain FEBS Journal Submitted
Periodical: FEBS Journal Index Medicus:
Authors: Ryan R.O., Redmond, K.A., Murphy, C., Kiss, R.S., Hauser, P., Guigard., Kay, C.M. ART
Yr: 2006 Vol: 273(3):558 Nbr: Abs: Pg:

Role of leucine zipper motif in apoE3 N-terminal domain lipid binding activity
Periodical: Biochim. Biophy. Index Medicus:
Authors: Yamamoto T. and Ryan R.O. ART
Yr: 2006 Vol: 1761 Nbr: Abs: Pg: 1100-1106