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The molecular basis of apoE and LDL receptor interaction

Institution: Children's Hospital Oakland Research Institute
Investigator(s): Taichi Yamamoto, Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15FT-0164 Award: $75,000
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

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 targets 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. We will conduct studies designed to ascertain the interaction between apolipoprotein E and low density lipoprotein receptor. We will evaluate the role of a specific architectural feature both of apolipoprotein E and low density lipoprotein receptor as a modulator of cholesterol homeostasis. These studies will increase our knowledge about the molecular mechanism between apolipoprotein E and low density lipoprotein receptor 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. Results obtained from my proposed research will be useful in the design of therapeutic strategies to prevent tobacco related disease.

Anionic Phospholipids inhibit apolopoproten E - Low density lipoprotein receptor interactions
Periodical: Biochem Biophys Res Commun Index Medicus:
Authors: Taichi, Y., Ryan, R.O. ART
Yr: 2007 Vol: 354 Nbr: 3 Abs: Pg: 820-4

Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor
Periodical: Analytical Biochemistry Index Medicus:
Authors: Yamamoto, T., Choi, H.W., Ryan, R.O. ABS
Yr: 2008 Vol: 372 Nbr: 2 Abs: Pg: 222-6