The overall object of this proposal is to investigate biochemical and molecular mechanisms through which individual fatty acids influence cellular activation and participate in immune and inflammatory responses. Novel fatty acids such as eicosapentaenoic acid (EPA), abundant in fish lipid, and gammalinolenic acid (GLA), found in particular plant seed oils, affect cell function in a manner that might make them useful therapeutic agents or patients with diseases, such as rheumatoid arthritis, which are characterize by chronic inflammation and tissue injury. Specifically, the effects of fatty acids on biochemical events (phospholipase A2 and C and protein kinase activities, phosphatidylinositol metabolism, diacylglycerol generation and changes in free cytosolic calcium and cyclic AMP concentrations) which serve to transduce receptor initiated signals to the nucleus, will be examined. Molecular mechanisms through which fatty acids alter lymphocytes activation will be investigated by measuring genes, such as cfos, junA and egr-1 whose protein products function as transcription factors, and interleukin-2 (IL-2) nad its receptor, IL-2Ralpha, which are expressed when T cells become committed to activation, and n-ras and c-fgr which are stimulated by IL-2. The effects of fatty acids on monocytes will also be investigated. Determination of monokine production and the ability of monocytes to function as accessory cells for lymphocytes will be examined. These studies should help define key mechanisms whereby naturally occurring fatty acids regulate human T lymphocytes activation and function. In turn, they might have clinical implications for development of novel benign therapy for inflammatory and autoimmune disorders.
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