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Lipid Peroxidation Unit

Christopher Ramsden, M.D., Ph.D., Chief

The central theme of the Lipid Peroxidation Unit (LPU) is to delineate the roles of lipid peroxidation and lipid-related degeneration in age-related diseases, with an emphasis on chronic pain and Alzheimer’s disease.

Background

Lipid peroxidation is a hallmark of aging and many of the most consequential age-related diseases, including chronic pain and neurodegenerative diseases.

Research Objectives

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

To translate these discoveries into targeted, safe, and effective diet and drug treatments.

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

Approach

The Unit applies an interdisciplinary, translational, team science approach—comprising randomized controlled trials, postmortem studies, synthetic and analytical chemistry, immunohistochemistry, and cellular 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 manipulation of 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 substrate manipulation as an adjunct strategy for managing treatment-resistant chronic headaches in collaboration with Doug Mann, M.D. and the Department of Physical Medicine and Rehabilitation Medicine. Dr. Ramsden is also the Co-PI of an RCT testing targeted substrate manipulation as a strategy for managing chronic Post-traumatic Headaches in military personnel in collaboration with Walter Reed, Fort Belvoir and Fort Bragg. Our Unit is also leading an NIH intramural RCT testing the effects of targeted substrate manipulation 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.

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.

Immunohistochemistry

Our team applies singe-marker immunohistochemistry (IHC) and multiplex-IHC to characterize lipid-related derangements in human brain regions involved in neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease.

Cellular models

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).

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.

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

Selected Publications

Ramsden CE, Zamora D, Faurot KR, MacIntosh B, Horowitz M, Keyes GS, Yuan Z, Miller V, Lynch C, Honvoh G, Park J, Levy R, Domenichiello AF, Johnston A, Majchrzak-Hong S, Hibbeln JR, Barrow DA, Loewke J, Davis JM, Mannes A, Palsson OS, Suchindran CM, Gaylord S, Mann JD. Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial. The BMJ. 2021; 374; n1448. https://www.bmj.com/content/374/bmj.n1448

Ramsden CE, Domenichiello AF, Yuan ZX, Sapio MR, Keyes GS, Mishra SK, Gross JR, Majchrzak-Hong S, Zamora D, Horowitz MS, Davis JM, Sorokin AV, Dey A, LaPaglia DM, Wheeler JJ, Vasko MR, Mehta NN, Mannes AJ, Iadarola MJ. A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. Sci Signal. 2017;10(493).

Ramsden CE, Faurot KR, Zamora D, Suchindran CM, Macintosh BA, Gaylord S, Ringel A, Hibbeln JR, Feldstein AE, Mori TA, Barden A, Lynch C, Coble R, Mas E, Palsson O, Barrow DA, Mann JD. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. 2013;154(11):2441-51.

Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK, Frantz RP, Davis JM, Ringel A, Suchindran CM, Hibbeln JR. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016;353:i1246.

Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR. 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. BMJ. 2013;346:e8707.