The mission of the LMIU is to delineate novel mechanisms linking lipids to inflammation, and to leverage this knowledge to develop and advance effective, safe treatments for age-related conditions with an emphasis on chronic pain, cardiovascular disease and neurodegenerative conditions. We apply an interdisciplinary, translational approach involving randomized controlled interventions, analytical and synthetic chemistry, and animal behavior studies. We recently published a manuscript in Science Signaling A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch, which describes substantial progress in this project. In brief, we applied an interdisciplinary approach to predict, discover and characterize a new family of endogenous lipid mediators derived from linoleic acid that are involved in inflammation, pain, and itch. We used a novel liquid chromatography-mass spectrometry assays developed in our laboratory, and samples collected from collaborative human studies and rodent studies, to show that these novel lipids: (1) are present in human and rodent tissues (especially inflamed skin); (2) activate cultured sensory neurons in a regio-selective manner; (3) cause thermal sensitivity and itch-related scratching behavior in rodents; (4) are reduced in human plasma by lowering their precursor in diet; and (5) that circulating levels of these mediators correlated with headache frequency and impact in patients with severe, chronic headaches. We are currently further characterizing the tissue distributions, receptors, actions, and signaling pathways for these novel lipid mediators, and for other related inflammatory oxylipins using an interdisciplinary, translational approach. In this respect, investigations are underway using postmortem human skin, coronary arteries, brain tissues, and numerous rodent tissues. We are employing rodent neuron assays, behavior studies, and receptor pull-downs in an attempt to identify the specific receptors for these endogenous compounds, and to investigate the signaling pathways, and activities of these and other lipid mediators in vascular tissues, skin, and peripheral and central nervous system tissues. We synthesized analogs of these mediators and other lipid mediators, and small molecules. We have begun to evaluate these as possible drug candidates using the same interdisciplinary approach. In addition, we filed a provisional patent application for the National Institute on Aging to protect the intellectual property for these endogenous compounds, analogs and small molecules. As an extension of this project in 2016, we predicted and synthesized another family of lipid mediators and are currently using a similar approach to investigate their tissue distributions, actions and signaling pathways. For the same project, we have acquired and equipped a new HPLC system capable of purifying and separating complex lipid species, and are in the process of upgrading our synthetic chemistry capabilities and room. These collective efforts will maximize the efficiency of our synthetic chemistry program, and facilitate achievement of our objectives of developing and advancing new treatments for age-related and inflammatory conditions.
