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Lipid Mediators, Inflammation, and Pain Unit

Christopher Ramsden, M.D., Chief

Christopher Ramsden, M.D., Chief

Mission

To improve the health of the Nation by reducing the burden of inflammatory and age-related diseases, with an emphasis on chronic pain, cardiovascular, and neurodegenerative diseases.

Research Objectives

The objectives of the Lipid Mediator, Inflammation, and Pain Unit (LMIU) are:  

  • 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 non-addictive diet and drug-based interventions to prevent and treat age-related diseases..

Approach

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

Portfolio/Research Areas

Randomized controlled trials

Our team is currently leading or collaborating on five 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 five 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 (Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial)  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” 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.

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 (A systems approach for discovering linoleic acid derivatives that potentially mediate 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.

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. 

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.

Team members

Christopher E. Ramsden, M.D.,
Principal Investigator and Head of the Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA, NIAAA

 

Dr. Ramsden shaking hands with Acting Surgeon General, Rear Admiral Sylvia Trent-Adams, during promotion to Commander in the United States Public Health Service. Dr. Ramsden is a Clinical Investigator in the Intramural Program of the National Institutes of Health, Commander in the Commissioned Corps of the U.S. Public Health Service (PHS), and Adjunct Faculty at UNC-Chapel Hill. After completing a medical internship, and then residency training in Physical Medicine & Rehabilitation at the Rehabilitation Institute of Chicago, he was a clinical research fellow at UNC-Chapel Hill before joining the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in 2009. In 2016, he was appointed to a Clinical Tenure-Track position as the Head of the Lipid Mediator, Inflammation, and Pain Unit, Laboratory of Clinical Investigation in the National Institute on Aging (NIA) in Baltimore, MD, with a joint Tenure-Track appointment in the Intramural Program of NIAAA in Bethesda, MD.  Dr. Ramsden leads an interdisciplinary, translational research program investigating the roles of lipid mediators and lipid-related mechanisms underlying the pathogenesis of chronic pain, inflammatory and neurodegenerative conditions. Dr. Ramsden also serves as a Medical Officer on the PHS-1 Rapid Deployment Force team in the Commissioned Corps, and recently deployed to provide medical coverage for the PHS response to Hurricanes Irma and Maria.

Gregory Keyes, M.S.,
Synthetic Chemist, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

 

Gregory Keyes in the laboratoryMr. Keyes earned his M.S. in Organic Chemistry from the University of New Brunswick, Canada in the lab of Dr. Ghislain Deslongchamps (Thesis title: Progress Towards a Tethered Adenine Receptor), where he studied molecular recognition with an emphasis on the design and total synthesis of modular scaffolds for the rapid assembly of abiotic receptors. Upon graduating in 2000 Greg began working as a Scientist at Cayman Chemical in Ann Arbor, MI, where he developed the commercial scale total syntheses of numerous catalog products, including leukotrienes, lipoxins, resolvins, and fluorescently labeled compounds and bioconjugates for use in ELISA kits. In 2008 Mr. Keyes became the first Manager of the Bioconjugate Chemistry group at Cayman while also continuing to research and develop the syntheses of novel new compounds, many in collaboration with external investigators including Dr. Charles Serhan at Harvard Medical School, and Dr. Christopher Ramsden at NIH. In 2016, Greg left Cayman Chemical and joined the newly formed LMIU Unit where he is currently using total organic synthesis to prepare newly discovered lipid mediators, stable analogs and other compounds of interest.

Zhi-Xin Yuan, Ph.D.,
Senior Analytical Chemist, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Dr. Yuan in the laboratoryDr. Yuan received her B.Sc. degree in Analytical Chemistry from Shengyang Pharmaceutical University (China) and her Ph.D. in Biochemistry from University of London (UK). Dr. Yuan worked as a principal scientist at Palatin Technology and study director and principal investigator at Quest Pharmaceutical Services. Her expertise includes metabolite structure elucidation and quantitation using tandem LC-MS with over 25 years of experience in bioanalysis. Dr. Yuan’s current research focuses on the development and application of tandem mass spectrometry methodologies in the lipidomics field for biomarker discovery, better understanding of disease mechanisms, and nutrition assessment. She led the development and validation of a UPLC-MS/MS method for simultaneous determination of 57 targeted oxylipins and 10 mono- and polyunsaturated fatty acid in plasma, and used mass spectrometry to identify endogenous mediators that were predicted by our group to be abundant in human skin.

Anthony Domenichiello, Ph.D.,
Postdoctoral Fellow, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Dr. Anthony Domenichiello in the laboratoryDr. Domenichiello earned his Ph.D. from the University of Toronto, working in the laboratory of Dr. Richard Bazinet where he studied brain fatty acid metabolism. In Dr. Bazinet’s lab, he conducted in vivo kinetic studies in awake animals, which required using a variety of analytical techniques (gas chromatography, high pressure liquid chromatography, ultra-high performance liquid chromatography and mass spectrometry) to measure synthesis rates and rates of uptake into the brain of polyunsaturated fatty acids. Additionally, Dr. Domenichiello examined the effects of dietary fatty acids on brain function, metabolism and biochemistry. Currently, Dr. Domenichiello is focused on studying the effects of oxidized lipid mediators on the nervous system with a particular focus on pain and Alzheimer’s disease. Specifically, he is using ultra high-performance liquid chromatography-tandem mass spectrometry to identify and measure novel oxidized lipid mediators in tissues and carrying out a variety of biochemical and rodent behavioral analyses to characterize the effects of oxidized lipid mediators in the body.

Kristen Maiden, B.S.,
Post baccalaureate Research Fellow, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Kristen Maiden in the laboratoryKristen Maiden received her B.S. in Biology and B.A. in Chemistry from the University of North Carolina Wilmington. While at UNCW, she studied receptor-binding affinities of synthetic tryptamine derivatives with neurological receptors in the laboratory of Dr. Jeremy Morgan. During her post-baccalaureate work at the NIA, she has helped to synthesize new lipid mediators of pain and inflammation under the guidance of Greg Keyes and assisted in various projects to elucidate the biochemical mechanisms of these compounds. She plans to pursue an M.D.

Kate DeMeulenaere, B.A.,
Post baccalaureate Research Fellow, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Kate DeMeulenaere in the laboratoryKate graduated with a B.A. in Chemistry from Carleton College in Northfield, MN. During her time at Carleton, she synthesized and tested a precious metal catalyst to understand its mechanism in adding hydrogen to a substrate. Since coming to the NIA for her post-bac, her research has focused on understanding how lipid mediators may contribute to the development and progression of neurodegenerative disorders. She plans to pursue a Ph.D. in biochemistry.

Jennifer Jensen, B.S.,
Post baccalaureate Research Fellow, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Jennifer Jensen on the intramural NIH campusJennifer is originally from Wilmington, North Carolina. She graduated with a B.S. in Biology and Psychology with Honors and Highest Distinction from the University of North Carolina at Chapel Hill. While at UNC, she conducted circuit level neuroscience, studying the role of a population of cells within the amygdala in binge-like eating behavior in mice. Since joining the Ramsden lab in August of 2017, she researches the role of lipid mediators in inflammation and nervous system disease-states, including pain, neurodegenerative diseases, and mood disorders. She plans to go on to pursue a Ph.D. in neuroscience.

Mark Horowitz, M.S.,
Data Specialist, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA

Mark HorowitzMark Horowitz provides a range of statistical and programming expertise and handles complex datasets. He is currently laying the foundation for publishing analysis code along with de-identified data for open publication of data in forthcoming publications.  Mark joined the Lipid Mediators, Inflammation and Pain Unit, LCI, NIA in 2016.  He has a B.S. in Civil Engineering from the University of California, Berkeley, and an M.S. in Environmental Sciences and Engineering from the University of North Carolina-Chapel Hill.

Daisy Zamora, Ph.D.,
Statistician, Special Volunteer, Lipid Mediators, Inflammation, and Pain Unit, LCI, NIA, Adjunct UNC-Chapel Hill

Daisy Zamora, PhDDr. Zamora studies diet-disease associations with a particular interest in causality.  Her previous work includes a longitudinal analysis of the effect of dietary guidelines on obesity and metabolic syndrome, and secondary analyses of randomized controlled trials on the effect of replacing saturated fat with linoleic acid on serum cholesterol and cardiovascular disease mortality.  She provides a range of statistical expertise, including hypothesis generation, study design, data analysis, and reporting methodologies. Dr. Zamora has been with the Lipid Mediators, Inflammation and Pain Unit, LCI, NIA since 2016.  She is also Assistant Professor (Adjunct) at UNC-Chapel Hill, where she completed a PhD in Nutrition Epidemiology and a post-doctoral fellowship in Integrative Medicine.

Findings and 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.

 

LMIU Research in the News

The Scientist - Linoleic Acid Derivatives Potentially Mediate Pain and Itch in the Skin

Scientific American -  Records Found in Dusty Basement Undermine Decades of Dietary Advice

Malcolm Gladwell, Revisionist History -  Episode 20: The Basement Tapes  

New York Times -  A Decades-old Study Rediscovered Challenges Advice On Saturated Fat

Washington Post -  This Study 40 Years Ago Could Have Reshaped The American Diet But It Was Never Fully Published

STATNEWS -  Unearthed Data Challenge Dietary Advice