Objective:
We previously found that docosahexaenoic acid (DHA) reduced the production of several markers for inflammation and serum triglycerides, and increased serum HDL in healthy men. Whether DHA will provide similar health benefits to men who are at increased risk for cardiovascular disease (CVD) because of elevated serum triglycerides is not known. Overall goal of our studies is to determine the effects of dietary fatty acids on immune and inflammatory responses and on risk factors of chronic diseases. Specific objectives are: 1. Determine effects of DHA supplementation on risk factors for CVD in hypertriglyceridemic men. 2. Determine effects of DHA and arachidonic acid on proliferation and differentiation of granulocytic precursor cells, and elucidate the mechanisms involved. 3. Determine whether different dietary fatty acids modulate the activation of Toll-like receptors, downstream signaling pathways, target gene expression and consequent cellular responses.

Approach:
Specific aim 1 will involve supplementing diets of hypertriglyceridemic men with DHA, and monitor its effects on a number on serum markers of inflammation (CRP, inflammatory cytokines, adhesion molecules, granulocyte numbers and maturation, scavenger receptor expression on monocytes), in vitro production of inflammatory markers (cytokines and eicosnoids), white blood cell genes whose expression will be up or down regulated by DHA, serum lipids and markers for diabetes. Specific aims 2 & 3 will involve feeding diets with different fatty acid compositions to animal models, and adding fatty acids to cultured cells. A number of molecular biological approaches including DNA microarrays, ectopic expression of genes, and transgenic animals will be used. Results from this study can validate novel markers for CVD and elucidate mechanisms by which dietary fatty acids modify risks of various chronic diseases. Formerly 5306-51530-011-00D (4/04).