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The Feinstein Institute for Medical Research

Empowering Imagination. Pioneering Discovery.
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Kevin J. Tracey, MD

President and CEO, The Feinstein Institute for Medical Research

Director, The Laboratory of Biomedical Science, The Feinstein Institute for Medical Research

Professor, Molecular Medicine & Neurosurgery, Hofstra North Shore-LIJ School of Medicine

Phone: (516) 562-2813
Email: kjtracey@nshs.edu

About the Investigator

Dr. Kevin Tracey studied chemistry at Boston College where he became convinced that the optimal path to improving medicine would be one that combined basic science research with direct patient care. He received his medical degree at Boston University, and trained in neurosurgery with Professor Russel Patterson at Cornell University Medical College. During this period Dr. Tracey collaborated with Anthony Cerami, Steve Lowry and others, and in 1986 he wrote a Science paper that defined the direct inflammatory action of tumor necrosis factor-alpha (TNF), and a Nature paper that reported the therapeutic effectiveness of monoclonal anti-TNF (1987). Dr. Tracey joined North Shore University hospital in 1992 and founded the laboratory of biomedical science, with a main focus in defining the body’s mechanisms that normally prevent the overproduction of TNF.

Interested in defining the body’s mechanisms that normally present the overproduction of TNF, Dr Tracey’s research led to the discovery of the inflammatory reflex, initially by electrically stimulating the vagus nerve to control macrophage TNF production via alpha-7 nicotinic receptors. These findings spanned immunology and neuroscience, and have engendered widespread interest in the fundamental role of neural reflexes in maintaining immunological homeostasis. He also discovered the direct inflammatory action of HMGB1, first reporting this in Science, which initiated a new field that has grown explosively. The identification of a critical cysteine of HMGB1 that interacts with TLR4 to stimulate cytokine release and inflammation reveals the critical role played by HMGB1 at the intersection of sterile and infectious inflammation.

Research Focus

The major focus of Dr. Tracey’s laboratory is inflammation, the physiological and immunological response to infection and injury, and the mechanism by which neurons control the immune system.

In the early 1980s, Tracey participated in the discovery of the direct inflammatory activity of tumor necrosis factor-alpha (TNF), and first reported that specific anti-TNF monoclonal antibodies can be effectively used as a therapeutic agent. A subsequently expanding field of research confirmed that TNF is a mediator of septic shock (similar to the effects of directly administering TNF to mammals), but not sepsis. This prompted the Tracey lab to search for another mediator of sepsis, culminating in 1999 with the identification of HMGB1, a protein previously known as a DNA-binding transcription factor, as a mediator and drug target in sepsis. The lab continues to focus on this activities and mechanisms of this molecule, and recently revealed the critical role played by the redox structure of the three cysteine residues which directly influence the biological activities of HMGB1 as a proinflammatory cytokine, and chemotactic factor.

Reasoning that evolution must have favored physiological mechanisms to maintain homeostasis, Dr. Tracey proposed a mechanism for how neural circuits control TNF and HMGB1 to maintain immunological homeostasis. Termed the inflammatory reflex, action potentials carried in the vagus nerve inhibit cytokine release and innate immune responses to invasive and injurious stimulating factors. The neurophysiological mechanism is dependent upon action potentials transmitted in the vagus nerve, which activate release of acetylcholine, the neurotransmitter that interacts with alpha-7 nicotinic receptors expressed on the cell surface of macrophages. The interaction of acetylcholine with alpha-7 nicotinic receptors prevents cytokine release by downregulating inflammasome activation.

Stimulating the vagus nerve inhibits potentially damaging cytokine responses, and protects against organ damage caused by unregulated or excessive cytokine release. In 2011, the lab reported the discovered of a memory T cell subset that secretes acetylcholine in the spleen when activated by signals arising in the vagus nerve. These T cells are regulated by incoming neurotransmission arising in the brain stem, and respond by producing the terminal neurotransmitter required to complete the inflammatory reflex. The neural circuit they discovered can be exploited to therapeutic advantage, because application of electrodes to stimulate the vagus nerve (vagus nerve stimulation) protects against damaging inflammation in experimental arthritis, colitis, ischemia, myocardial infarction, congestive heart failure, and other conditions. In November 2012, the lab participated in reporting the first successful clinical trial demonstrating that vagus nerve stimulation can be effective in methotrexate-resistant rheumatoid arthritis patients, as presented at the annual meeting of the American College of Rheumatology.

The importance of the inflammatory reflex in controlling inflammation establishes that the immune system does not function autonomously. Thus, immune responses and adaptation to infection and injury are integrated into host physiology, and coordinated by physiological units of reflex action.

Lab Members

Sangeeta S Chavan, PhD
Associate Investigator / Lab Manager
Research: Dr. Chavan studies molecular and physiological basis of how neural circuits regulate immune responses. She is also interested in studies of HMGB1 biology and its therapeutic potential in the treatment of inflammatory diseases.
E-mail: schavan@nshs.edu

Huan Yang, PhD
Associate Investigator
Research: Dr. Yang is interested in studying role of HMGB1 in sepsis pathogenesis.
E-mail: hyang@nshs.edu

Valentin Pavlov, PhD
Associate Investigator
Research: Dr. Pavlov studies cholinergic mechanisms of regulation of innate immunity and inflammation and their therapeutic implications in inflammatory and metabolic disorders.
E-mail: vpavlov@nshs.edu

Mahendar Ochani, MD
Assistant Investigator
Research: Dr. Ochani is an animal surgeon who is involved in day-to-day animal experiments.
E-mail: mochani@nshs.edu

Peder Olofsson
Institute Scientist
Research: Dr Olofsson studies how nerve reflexes regulate the body’s defense to microorganisms and injury.
E-mail: lolofsson@nshs.edu

Jin Hua Li, MS
Research Scientist
Research: Mr. Li is involved in purification of recombinant proteins and various polyclonal and monoclonal antibodies.
E-mail: jli@nshs.edu

Zhonglian Ju
Research Scientist
Research: Dr. Ju is interested in studying mechanisms in HMGB1 mediated inflammation and developing novel therapies against inflammatory diseases.
E-mail: zju@nshs.edu

William Hanes
Research Scholar
Research: Mr Hanes is interested in the interaction between the immune and nervous systems, in particular antibody response modulation and Type I Diabetes.
E-mail: whanes@nshs.edu

Meghan E. Dancho
Research Assistant
Research: Ms Dancho is involved in studies of neural cholinergic mechanisms that control inflammation.
E-mail: mdancho@nshs.edu

Harold Silverman
Research Assistant
Research: Mr. Silverman studies neural cholinergic mechanisms controlling inflammation in the context of endotoxemia and sepsis.
E-mail: hsilverman@nshs.edu

Ben Lu
Elmezzi Scholar
Research: Dr Lu studies the regulation of inflammasome activation and HMGB1 release.
E-mail: blu@nshs.edu

Sergio Valdes-Ferrer
Elmezzi Scholar
Research: Dr Valdes-Ferrer studies the role of HMGB1 on stress erythropoiesis, erythrocyte proliferation and differentiation. His other interest is in the role of sepsis on the accumulation of toxic forms of β-amyloid during and after sepsis.
E-mail: svaldesfer@nshs.edu

La Queta Hudson, MS
Hofstra PhD Student
Research: Ms Hudson studies the role of Pigment Epithelium Derived Factor in metabolic diseases.
E-mail: lhudson@nshs.edu

Education

Boston College
Degree: BS
Field of Study: Chemistry

Boston University
Degree: MD
Field of Study: Medicine

Cornell University Medical College
Degree: Residency
Field of Study: Neurosurgery

Appointments

1992 Director, Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY
2000-2005 Program Director, North Shore-LIJ General Clinical Research Center, Manhasset, NY
2006 President, The Feinstein Institute for Medical Research, Manhasset, NY
2006 Professor and President, The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY
2008 Dean of Research, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY

Honors and Awards

2001 American Society for Clinical Investigation
2003 Annual Clinical Science Lecture, Karolinska Institute, Stockholm
2005 Highly Cited Researcher (Immunology)
2005 Editor in Chief, Molecular Medicine
2007 National Institutes of Health Directors’s Lecture Series, The DeWitt Stetten, Jr. Lecture
2009 Doctor honoris causa, Karolinska Institute
2009 Association of American Physicians

Publications
  1. Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, ReardonC , Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. “Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.” Science. 2011 Oct 7;334(6052):98-101. doi: 10.1126/science.1209985. Epub 2011 Sep 15. PubMed PMID: 21921156.
  2. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. “HMG-1 as a late mediator of endotoxin lethality in mice. Science.” 1999 Jul 9;285(5425):248-51. PubMed PMID: 10398600.
  3. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ 3rd, Zentella A, Albert JD, et al. “Shock and tissue injury induced by recombinant human cachectin.” Science. 1986 Oct 24;234(4775):470-4. PubMed PMID: 3764421.
  4. Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundbäck P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou Y, Erlandsson-Harris H, Yang H, Ting JP, Wang H, Andersson U, Antoine DJ, Chavan SS, Hotamisligil GS, Tracey KJ. “Novel role of PKR in inflammasome activation and HMGB1 release.” Nature. 2012 Aug 30;488(7413):670-4. doi: 10.1038/nature11290. PubMed PMID: 22801494.
  5. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. “Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature.” 2003 Jan 23;421(6921):384-8. Epub 2002 Dec 22. PubMed PMID: 12508119.
  6. Tracey KJ. “The inflammatory reflex. Nature.” 2002 Dec 19-26;420(6917):853-9. Review. PubMed PMID: 12490958.
  7. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.” Nature. 2000 May 25;405(6785):458-62. PubMed PMID: 10839541.
  8. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. “Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.” Nature. 1987 Dec 17-23;330(6149):662-4. PubMed PMID: 3317066.

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