Deciphering the metabolism and protective role of the essential nutrient, DHA - PROJECT SUMMARY Nutritional consumption of an essential lipid nutrient, the omega-3 docosahexaenoic acid (DHA), is inversely correlated with numerous diseases, yet due to its rarity in western diets an estimated 80% of the US population is nutritionally deficient in DHA. Because DHA is well documented to provide many health benefits, the exciting prospect that dietary lipid augmentation may be an effective therapeutic strategy to prevent and treat disease has been of therapeutic interest. However, effective therapeutic progress has been stymied by critical limitations in the field, including: 1) a fundamental gap in our understanding of how DHA metabolism is regulated in pre- and post-disease states; and 2) a lack of strong pre-clinical models to mechanistically test the effects of DHA metabolism on health. This research team has overcome these barriers by targeting an enzyme, long-chain acyl-CoA synthetase 6 (ACSL6), to generate a novel preclinical model with a ~50% deficit in DHA specifically in neurons independent of dietary manipulations. Preliminary data demonstrate the critical role of lipid metabolism in health evidenced by accelerated disease due to the loss of ACSL6. The team proposes to test the overall hypothesis that ACSL6-mediated DHA metabolism protects against disease. This work will (Aim 1) determine the role that DHA metabolism plays in neurological health, derived the regulatory metabolism that controls the accrual and turnover of neural DHA, and (Aim 3) test the novel hypothesis that DHA- lipid mediators in the membrane-bound state serve as a readily available pool of protective agents. (Aim 2) determine The proposed work will unmask fundamental breakthroughs, resolve long-standing unknowns, and test novel hypotheses regarding the importance of DHA metabolism in pressing aspects of health and disease.
