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Targeting vascular lesions in hypercholesterolemic zebrafish

Institution: University of California, San Diego
Investigator(s): Longhou Fang, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18FT-0137 Award: $134,500
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Cholesterol and other lipids are essential nutrients delivered to different parts of the body by lipoproteins, but higher levels of cholesterol in blood lead to excessive lipid accumulation in arteries. This, in turn, leads to vascular inflammation and initiates the development of atherosclerosis, the major cause of heart attack and stroke in humans. Cigarette smoking and environmental smoking greatly accelerate the development of atherosclerosis and intensify its clinical complications, in large part because the cigarette smoke contains many free radicals, which oxidize lipids and make lipoproteins even more harmful to arteries.

Many researchers use mice and rabbits to model many aspects of human atherosclerosis, but detailed microscopic examination of plaques is possible only after the animal is sacrificed. In contrast, I propose to use zebrafish (Danio rerio) as an animal model for atherosclerosis research. Zebrafish are small, fresh water fish that are optically clear until one month old, which makes it possible to temporarily immobilize the fish (anesthesia) and study it alive under a microscope. Many genetic and physiologic features of fish cardiovascular system are identical or very similar to those in humans. My preliminary studies show that feeding zebrafish a high-cholesterol diet results, as in mice and humans, in high levels of cholesterol in blood, remarkable lipoprotein oxidation (like the oxidation induced by cigarette smoke) and accumulation of lipid in the blood vessel wall (resembling very early plaques in people).

Our collaborators have discovered that humans and mice produce defensive molecules - antibodies - that bind to and neutralize oxidized lipoproteins. These antibodies can be used for better imaging of unstable plaques (angiography), the plaques that rupture and cause myocardial infarctions, because these plaques accumulate large amounts of oxidized lipoproteins. I propose to use the zebrafish model and these unique antibodies to develop - rapidly and efficiently - angiographic applications that can be then translated into clinical practice. I will be able to monitor binding of these antibodies to vascular lesions in a live animal and with high resolution, which is impossible to do using mice. Moreover, I will make a transgenic (i.e. carrying an additional gene) zebrafish, which will be producing such an antibody in its own body in an inducible fashion. The antibody will be produced only after the fish will be transferred for a short time from its normal 82 degree Fahrenheit water to a bath of water at 99 degree Fahrenheit. We will literally see this antibody in the zebrafish because it will be engineered to emit green light under a microscope. This technique will greatly facilitate the development of imaging agents for the angiography and help understand how they work. Furthermore, I will test if these antibodies can help reduce atherosclerosis. I will make zebrafish produce the antibody all the time during feeding them high-cholesterol food and will check if this will reduce the formation of vascular lesions.

I believe that the field of atherosclerosis research will benefit from the zebrafish animal model that allows a dynamic and live observation of lipid accumulation and vascular inflammation, two essential features of atherosclerosis. My studies will help develop new clinical applications of specific antibodies for angiography and new approaches to atherosclerosis treatment. This work will aid in diagnosis and treatment of the most dangerous tobacco-related disease in California.