The mission of the LMIU is to discover new mediators and mechanisms linking lipids to inflammatory and age-related diseases, and to translate these discoveries into targeted, safe, and effective nutrition-based and drug treatments. Our long-term objective is to develop and advance non-addictive diet and drug-based interventions to prevent and treat age-related diseases. We apply an interdisciplinary, translational approachcomprising randomized controlled trials, other clinical and postmortem studies, missing data recovery, synthetic and analytical chemistry, animal models, immunohistochemistry, and cellular and ex vivo assaysto achieve these objectives. Randomized controlled trials Our team is currently leading or collaborating on several randomized controlled trials testing the clinical efficacy and biochemical effects of targeted alterations in dietary fatty acids, which are precursors to bioactive lipid mediators including oxylipins and endocannabinoids. These trials include a total of more than 500 randomized participants, including 350 suffering with chronic pain syndromes that are refractory to conventional medical management. These five trials grew out of the promising results of small randomized trial conducted at UNC-Chapel Hill testing targeted dietary manipulation as an adjunct strategy for managing treatment-resistant chronic headaches in collaboration with Doug Mann, M.D., and the Program on Integrative Medicine, Department of Physical Medicine and Rehabilitation Medicine. We are leading an NIH intramural RCT testing the effects of targeted alterations in dietary fatty acids on endocannabinoids, craving, satiety, and body composition. This trial is led by NIAAA and includes investigators from NIA, NIDDK, the NIH Clinical Center, and UNC-Chapel Hill. Missing Data Recovery Our team led the recovery and publication of missing data from two landmark randomized controlled diet-heart trialsthe Minnesota Coronary Experiment and the Sydney Diet Heart Studythat were not fully published by the original investigators. Findings from these two RCTs contributed to a re-evaluation of the traditional understanding of the diet-heart hypothesis. Our team is currently leading the recovery of additional missing clinical trial datasets that may have important public health implications. Discovery of new mediators and mechanisms linking lipids to disease Our team recently discovered of a new family of lipid mediators that are abundant in inflamed human skin and other tissues, which appear to play a role in pain and itch. Efforts are underway to further characterize the biological actions of these novel lipids, and to identify their receptors and signaling pathways responsible for their activities. We are currently using a similar approach to discover endogenous mediators of inflammation and degeneration in the brain, spinal cord, and peripheral nervous system tissues. Drug discovery Our team uses the interdisciplinary, translational approach described above to inform the design, total synthesis, and activity screening of stable analogs and small molecules as potential drug candidates. The long-term goal of these efforts is to develop targeted, effective, non-addictive drugs to treat chronic pain and neurodegenerative diseases. Animal models Our team is testing the effects of dietary manipulation, inflammatory stimuli, newly discovered lipid mediators, and novel drug candidates using rodent models at NIA, and in collaboration with NCCIH, NHLBI, and the Mishra Lab at N.C. State. Analytical chemistry Our team applies liquid chromatography-tandem mass spectrometry and related techniques to identify and quantify bioactive lipid mediators, pathway precursors, and inactivation products in human and rodent tissues. These approaches provide key biochemical insights into the mechanisms of action linking lipid mediators and their precursor fatty acids to inflammation, pain, and related clinical endpoints in randomized controlled trials and other studies. Immunohistochemistry Our team applies immunohistochemistry and related techniques to characterize lipid-related derangements in human and animal tissues, and to investigate the effects of lipid mediators and their dietary precursors on neuro-histological endpoints. These collective efforts are directed toward discovery of new mediators and mechanisms underlying age-related diseases, and the translation of findings into effective, non-addictive treatments for chronic pain, cardiovascular and neurodegenerative diseases.