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Lipid Mediators, Inflammation, and Pain Unit

Christopher Ramsden, M.D., Chief

The central theme of the Lipid Mediator, Inflammation, and Pain Unit (LMIU) is to delineate the roles of lipid peroxidation and degradation in inflammatory and age-related diseases, with an emphasis on chronic pain, cardiovascular, and neurodegenerative diseases. 

Research Objectives

To discover new mediators and mechanisms linking lipids to inflammatory and age-related diseases.

To translate these discoveries into targeted, safe, and effective nutrition-based and drug treatments.

Our long-term objective is to develop and advance targeted, non-addictive diet- and drug-based interventions to prevent and treat age-related diseases.

Approach

The Unit applies an interdisciplinary, translational, team science approach—comprising randomized controlled trials and other clinical studies, postmortem studies, missing data recovery, synthetic and analytical chemistry, immunohistochemistry, and animal models—to achieve these objectives. 

Selected Ongoing Projects

Randomized controlled trials

Our team is currently leading or collaborating on several randomized controlled trials (RCTs) 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 RCTs 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.

Analytical chemistry approaches for profiling labile oxidized lipid mediators

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.

Discovery of new mediators and mechanisms linking lipids to disease

Our team recently discovered of a new family of lipid mediators derived from linoleic acid 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.

Synthetic Chemistry and 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. 

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.

Cellular and ex vivo assays

Our Unit is testing the effects of oxidized lipids and lipid-related signaling pathways on neuronal and glial cell viability and activities using differentiated human neural stem cells derived from circulating progenitor cells (provided in collaboration with NINDS).  We are also testing the effects of newly discovered and known lipid mediators on sensory nerve activation in collaboration with the Mishra Lab at N.C. State and Suzanne Doolen at the University of Kentucky. 

Missing Data Recovery

Our team led the recovery and publication of missing data from two landmark randomized controlled “diet-heart” trials—the Minnesota Coronary Experiment and the Sydney Diet Heart Study—that 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.

In summary, the central theme of the LMIU is to delineate the roles of lipid peroxidation and degradation, and to develop and advance new treatments for inflammatory and age-related diseases, with an emphasis on chronic pain, cardiovascular, and neurodegenerative diseases.

Selected Publications

Ramsden, C.E., Domenichiello A.F., Yuan Z.X., Sapio M., Keyes G.S., Mishra S.K., Gross J.R., Majchrzak-Hong S., Zamora D., Horowitz M.S., Davis J.M., Sorokin A.V., Dey A., LaPaglia D.M., Wheeler J., Vasko M.R., Mehta N.N., Mannes A.J., Iadarola M.J.  A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. Sci Signal. 2017 Aug 22;10(493). 

Ramsden, C. E., Faurot, K. R., Zamora, D., Suchindran, C. M., MacIntosh, B. A., Gaylord, S., … Mann, J. D. (2013). Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial. Pain, 154(11), 10.1016/j.pain.2013.07.028. doi: 10.1016/j.pain.2013.07.028

Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., … Hibbeln, J. R. (2016). Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). The BMJ, 353, i1246.

Ramsden, C. E., Zamora, D., Leelarthaepin, B., Majchrzak-Hong, S. F., Faurot, K. R., Suchindran, C. M., … Hibbeln, J. R. (2013). Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. The BMJ, 346, e8707

Ramsden, C. E., Ringel, A., Majchrzak-Hong, S. F., Yang, J., Blanchard, H., Zamora, D., … Taha, A. Y. (2016). Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes? Molecular Pain, 12.