SBIR-STTR Award

High levels of low density lipoprotein (LDL), cholesterol and triglycerides have been associated with an increase in cardiovascular disease. Drugs such as cholesterol-lowering statins and triglyceride-lowering fibrates have led to a reduction in coronary heart disease. Although current drugs have enjoyed some success, a need exists for improved lipid management and reduced side effects. Zygogen is developing a novel in vivo approach to identifying potential lipid-lowering drugs using Zebrafish, called Z-Lipotrack. Lipid processing is highly conserved in the Zebrafish. Because Zebrafish larvae are essentially transparent, lipid processing can be readily observed in the whole organism, with the aid of fluorescent lipid reporters. The goal of the proposed research is to develop Z-Lipotrack technology for use in high throughput compound screening, with the ultimate aim of discovering better drugs for lowering lipid levels. The proposed work will validate Z-Lipotrack as a compound screening tool. This includes testing additional control compounds, characterizing compounds identified in a small but diverse library of marketed drugs, and quantifying the fluorescent read-out in an automated fashion. Due to the high fecundity of Zebrafish, high throughput drug screening using Zebrafish larvae is feasible and could dramatically increase the chances of finding important new drugs

Cardiovascular disease is the number one cause of death in the United States today. High levels of cholesterol and triglycerides have been identified as major contributing factors to heart disease. Furthermore, lipid-lowering drugs such as statins and fibrates have been shown to reduce the incidence of coronary disease. Although current drugs have enjoyed some success in this area, a need remains for improved drugs with fewer side effects. The goal of this proposal is to develop a fluorescent zebrafish assay (Z-Lipotrack) to identify new drugs for lipid management. The zebrafish has many advantages to model vertebrate diseases. In particular, they process lipids through the digestive system in a manner similar to mammals. Because zebrafish larvae are essentially transparent, such processing can be readily observed in the whole organism, with the aid of fluorescent lipid substrates, which are swallowed by the zebrafish larvae and transported from the intestine to the liver and gall bladder. To increase the usefulness of Z-Lipotrack for high throughput drug screening, a fluorescent plate reader will be developed to automatically image the Z-Lipotrack assay. Secondly, the use of Z-Lipotrack for compound optimization will be evaluated. Finally, compounds identified as potential lipid-lowering drugs in Phase 1will be fully characterized and optimized through the use of medicinal chemistry to identify lead compounds for further animal and human studies.

Public Health Relevance:
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Thesaurus Terms:
Antihypercholesterolemic Agent, Biomedical Automation, Disease /Disorder Model, Drug Discovery /Isolation, Drug Screening /Evaluation, Lipid Metabolism, Zebrafish Bioassay, Cardiovascular Disorder, Computer Program /Software, Computer System Design /Evaluation, Fluorescent Dye /Probe, Larva, Pharmacokinetics Biotechnology, High Throughput Technology, Thin Layer Chromatography