My laboratory studies the health benefits of omega-3 polyunsaturated fatty acids and the mechanisms of their action. We are particularly interested in the beneficial effects of these lipids on cardiovascular disease, cancer and inflammatory diseases. Studies are performed at the molecular, cellular, animal and human levels. Techniques employed are those of molecular biology, cell biology, biochemistry and biophysics, including microarray analysis, adenoviral gene transfer and transgenic animals.
We have been investigating the cardiac antiarrhythmic effects of omega-3 polyunsaturated fatty acids for the last 10 years. Through a series of experiments, we have documented the efficacy of the protective effect of n-3 fatty acids against arrhythmias induced by various drugs/agents or by ischemia. (A clinical trial is underway.) Our findings obtained so far have greatly advanced our understanding of how these fatty acids can prevent cardiac arrhythmias, the main cause of sudden cardiac death. Our ongoing studies focus on identification of the factors/ pathways that mediate the protective effects of omega-3 fatty acids, aiming at elucidation of the molecular mechanism of their action.

We have recently initiated a new project to explore the feasibility of modifying fatty acid composition of mammalian cells (i.e. increasing the content of omega-3 fatty acids and decreasing the level of omega-6 fatty acids) using a genetic approach. (So far the only possible way to enrich the tissues with omega-3 fatty acids in mammals has been dietary provision of omega-3 fatty acids). By using viral strategies, we have demonstrated that gene transfer of C. elegans omega-3 fatty acid desaturase into mammalian cells, which lack this enzyme, rendered cells capable of converting n-6 fatty acids to corresponding n-3 fatty acids, leading to a balanced omega-6/omega-3 fatty acid ratio and beneficial effects on cell function, with no need of supply of exogenous fatty acids. We are currently evaluating the utility of this gene transfer as a novel means to provide the preventive and therapeutic effects of omega-3 fatty acids. In addition, we have created transgenic mice expressing the omega-3 desaturase. We will use the transgenic animals to address the importance of omega-3 fatty acids and omega-6/omega-3 ratio in disease-prevention and treatment. This model also provides a new strategy for producing omega-3-enriched foodstuff (e.g. meat, milk and eggs) by generating large transgenic animals (e.g. cow, pig, sheep and chicken) with the n-3 desaturase gene.

Another project in my laboratory is to study the interaction between retinoids and the mannose-6-phosphate/insulin-like growth factor -II receptor (M6P/IGF2R) and its role in cell growth regulation. We discovered a novel retinoid-response pathway mediated by the M6P/IGF2 receptor. Using adenoviral-mediated gene transfer and ribozyme technologies, we demonstrated a key role for the M6P/IGF2 receptor in the regulation of cell death. The work may have important implications for fields ranging from development to cancer biology.

References:

1. Kang JX and Leaf A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc Natl Acad Sci USA 1994;91:9886-9890.
2. Kang JX, Xiao YF and Leaf A. Free long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci USA 1995;92:3997-4001
3. Kang JX and Leaf A. The antiarrhythmic effects of polyunsaturated fatty acids; Recent studies. Circulation 1996;94:1774-1780
4. Kang JX, Li Y, Leaf A. Mannose 6-phosphate/insulin-like growth factor II receptor is a novel receptor for retinoic acid. Proc. Natl. Acad. Sci. USA 1997;94:13671-13676.
5. Zang Y, Beard RL, Chandraratna RAS, and Kang JX. Evidence of a Lysosomal Pathway for Apoptosis Induced by the Synthetic Retinoid CD437 in Human Leukemia HL-60 Cells. Cell Death and Differentiation 2001;8(5):477-485.
6. Kang ZB, Ge Y, Chen ZH, Brown J, Laposata M, Leaf A and Kang JX. Adenoviral gene transfer of C. elegans n-3 fatty acid desaturase optimizes fatty acid composition in mammalian cells. Proc. Natl. Acad. Sci. U S A. 2001;98:4050-4054.
7. Ge Y, Wang XY, Chen ZH, Landman N, Lo EH and Kang JX. Inhibition of neuronal apoptosis by adenoviral gene transfer of C. elegans n-3 fatty acid desaturase. J.Neurochem. 2002; 82(6): 1360-1366.
8. Kang JX. The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cell Function: The Gene Transfer of Omega-3 Fatty Acid Desaturase. World Rev. Nutr. Diet 2003, Vol. 92 (In press)