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Novel Mechanisms in Resolution of Inflammation
Tuesday, January 25, 2011
Presented By
Uncontrolled, chronic inflammation is now considered a major component of many widely occurring diseases, including asthma, atherosclerosis and peripheral vascular disease, Alzheimer’s disease, and cancer. These diseases now join the group of disorders, such as arthritis and periodontal disease, which have been well-recognized as being "inflammatory diseases." While inflammation may not be the causative factor in these diseases, it is now believed to contribute to disease progression, tissue dysfunction, and ultimately organ failure in these diseases. Resolution of inflammation was once considered a passive process. In recent years, evidence has emerged that this is a biochemically active process and more recent results have established some of the chemical mediators involved. Elucidation of biochemical pathways contributing to the resolution of inflammation has provided many new anti-inflammatory targets and an opportunity for resolution-based pharmacology for the treatment and prevention of inflammatory disorders. The objective of this symposium is to provide a review of recent discoveries and advances in the field, and to show how this work is translating into new approaches and new pharmacology to treat old diseases, including first-in-human clinical trial results. Suggested speakers are leaders in the field with a particular interest in translating their findings into new and effective medicines.
Presented by
This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.
For a list of additional sponsors, please click the Sponsors tab.
Agenda
*Presentation times are subject to change.
12:30 PM | Registration |
1:00 PM | Introduction |
1:10 PM | Mechanisms and Consequences of Defective Inflammation Resolution in Atherosclerosis |
1:45 PM | Novel Mechanisms in the Resolution of Acute Inflammation |
2:20 PM | Endogenous Anti-Inflammation and Resolution: Players and Receptors |
2:55 PM | Coffee Break |
3:25 PM | Resolvins and Protectins in Ocular Wound Healing, Inflammation and Angiogenesis |
4:00 PM | From Bench to Clinic: Resolvins as New Therapeutics |
4:35 PM | Panel Discussion |
5:00 PM | Program Ends |
Speakers
Organizers
Charles N. Serhan, PhD
Harvard University, Brigham & Women's Hospital
George Zavoico, PhD
MLV
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Per Gjorstrup, MD, PhD
Resolvyx Pharmaceuticals
Per Gjorstrup, MD, PhD, is currently Chief Medical Officer of Resolvyx Pharmaceuticals, which was founded based on the discovery of resolvins and protectins, and their potential as therapeutics for a wide range of diseases. Under Dr Gjorstrup's leadership two drug candidates from the resolvin class of molecules have moved into clinical development, and with one, for the treatment of dry eye, ready to enter phase 3 clinical studies. Dr Gjorstrup has an extensive background in translational and clinical drug development and has in leading positions with AstraZeneca, Pharmacia, Biogen, and Micromet been instrumental in bringing 6 first-in-class lead compounds from preclinical translational research into phase 2 clinical proof of concept studies, and beyond. Dr Gjorstrup received his MD and PhD degrees at University of Lund, Lund, Sweden. He has published extensively on preclinical and clinical drug development and is the holder of several patents.
Karsten Gronert, PhD
University of California, Berkeley
Born in Germany in 1965, Karsten Gronert received his BS in biology with a minor in chemistry in 1987, and his MS in biology in 1990, from the University of Texas at El Paso. Karsten obtained his PhD in cell physiology in 1995 from New Mexico State University and then moved to Boston for postdoctoral training in inflammation and molecular pharmacology at Harvard Medical School and Brigham and Women's Hospital. At Harvard Medical School he was promoted to instructor in 1999 and assistant professor in 2002. He moved to New York Medical College in 2003, and in 2005 was promoted to associate professor in pharmacology and ophthalmology. Karsten Gronert relocated his research program to the University of California, Berkeley and joined the faculty in the Vision Science Program in the fall of 2007 and was appointed as the Solon M. and Pearl A. Braff Chair in Clinical Optometric Science in January 2008. His National Eye Institute (NEI) sponsored research program is focused on defining the role of lipid signals in inflammatory/immune responses of the eye and developing novel therapeutic approaches to limit the consequence and progression of ocular injury and diseases.
Mauro Perretti, PhD
Queen Mary University of London
Pharmacologist. Interests in mechanisms of experimental and translational inflammation, with attention to the identification of new targets amenable to drug discovery.
Pioneered the area of endogenous inflammatory resolution (see TiPS 1997, Faseb J 2007). Current research focusing on anti-inflammatory pro-resolving mediators (e.g. annexin A1, calcitonin, ACTH, galectins, resolvins, chemerin) and their GPCRs (FPR2, MC1, MC3 and MC5, CTR, ChemR23, etc...).
Fellow of the British Pharmacological Society (from 2005)
Fellow of the Academia Europea (from 2010)
Active Grants: Wellcome Trust, Arthritis Research UK, British Heart Foundation, BBSRC, Industrial.
Over 220 Peer-reviewed Publications. 7 patent applications (3 licenced).
Charles N. Serhan, PhD
Harvard University, Brigham & Women's Hospital
Charles N. Serhan is the Simon Gelman Professor of Anaesthesia (Biochemistry and Molecular Pharmacology) at Harvard Medical School and Professor of Oral Medicine, Infection and Immunity at HSDM, Harvard University. Since 1995, he has been the Director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women's Hospital in Boston. Professor Serhan received his Bachelor's degree in biochemistry from Stony Brook University, New York, and went on to receive his doctorate in experimental pathology and medical sciences from New York University (NYU) School of Medicine. From 1981-86, he was a visiting scientist at the Karolinska Institutet and post-doctoral fellow with Professor Bengt Samuelsson. In 1996, he received an honorary degree from Harvard University.
Dr. Serhan was awarded an NIH MERIT Award (2000), the MacArthur Research Service Award in 2003, and the Outstanding Scientist Award in Inflammation Research at BioDefense, 2004. He delivered the 2005 Kreshover Lecture at NIH, received the LSU Chancellor's Award in Neuroscience in 2006, and in 2007 the Dart/New York University Biotechnology Outstanding Achievement Award. In 2008, he delivered the Sir John Vane Memorial Lecture and received the William Harvey Outstanding Scientist Medal 2008. In 2010, Dr. Serhan received the Kern Lecturer in recognition of outstanding research in the science of lipids and lipoproteins and he delivered the Kopriva Memorial Lectureship in Interdisciplinary Biomedical Sciences at Montana State University. He also received the Society for Leukocyte Biology 2010 Bonazinga Award for excellence in leukocyte biology research, the highest honor that the society can bestow.
Professor Serhan serves on several International Organizing Committees and has been a session chair and keynote lecturer at many meetings. He is a founder and board member of the Eicosanoid Research Foundation. He is a member of several societies and editorial boards, including the ASBMB, Inflammation (Associate Editor), American Society for Pharmacology and Experimental Therapeutics, AAI, ASIP and the Journal of Experimental Medicine (Editorial Board). Since 2007 he has served on the Foundation for the NIH Biomarkers Consortium.
Dr. Serhan led the NIH Program Project "Molecular Mechanisms in Leukocyte-Mediated Tissue Injury" (P01-DE13499), and recently serves as Principal Investigator/Program Director of the Center grant entitled "Specialized Center for Oral Inflammation and Resolution" (P50-DE016191) and NS067686, GM038765, and DK07448.
Professor Serhan has authored 384 publications, 5 books, and over 219 US patents.
Ira Tabas, MD, PhD
Columbia University
Dr. Tabas received his medical degree and his doctorate in biochemistry from Washington University in St. Louis, Missouri. Subsequently, he completed an internship and residency in internal medicine and a fellowship in endocrinology and metabolism at Columbia University Medical Center in New York City. During that period, Dr. Tabas also conducted a postdoctoral fellowship in the laboratory of Dr. Alan Tall in the Department of Medicine at Columbia University. He joined the Columbia faculty in 1985 and is currently the Richard J. Stock Professor and Vice-Chair of Research in the Department of Medicine and Professor of Pathology & Cell Biology (in Physiology and Cellular Biophysics).
Dr. Tabas' research focuses on the role of macrophages in atherosclerosis, with an emphasis on intracellular cholesterol metabolism in macrophages and the mechanisms and consequences of macrophage cell death in advanced atherosclerotic lesions. He has lectured worldwide and published numerous articles on the role of lipids and macrophages in atherosclerosis. His research has been published in Nature Cell Biology, Nature, Nature Reviews Immunology, Cell Metabolism, Proceedings of the National Academy of Science USA, Journal of Cell Biology, and Journal of Biological Chemistry. He has served on the editorial board of the Journal of Biological Chemistry, and he was Deputy Editor of the Journal of Clinical Investigation from 2002-2007.
Dr. Tabas' honor include the American Heart Association Established Investigator Award, the Columbia University Doctor Harold and Golden Lamport Research Award, the American Heart Association/ATVB Council Special Recognition Award, and the Richard J. Stock Professorship in the Department of Medicine of Columbia University. He was elected to both the Society for Clinical Investigation and the Association of American Physicians.
Edward Thorp, PhD
Columbia University
Dr. Thorp received his PhD in Microbiology and Immunology from Loyola University Chicago. Subsequently, he conducted a postdoctoral fellowship in the laboratory of Dr. Ira Tabas in the Department of Medicine at Columbia University. This summer, he will begin as Assistant Professor in the Department of Pathology in the Feinberg School of Medicine at Northwestern University in Chicago.
Dr. Thorp's research focuses on the role of inflammation resolution during cardiovascular disease. He has published in Cell Metabolism and Circulation and regularly reviews articles for ATVB and the Journal of Immunology.
Dr. Thorp's honors include receipt of the American Heart Association National Scientist Development Grant. He is currently an NIH Pathway to Independence Fellow.
Sponsors
For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.
Academy Friend
Bristol-Myers Squibb Research and Development
Grant Support
This activity is supported by an educational donation provided by Amgen.
This event is funded in part by the Life Technologies™ Foundation.
Abstracts
Mechanisms and Consequences of Defective Inflammation Resolution in Atherosclerosis
Ira Tabas, MD, PhD, Columbia University, New York, NY
A majoring driving force in the progression of atherosclerosis is a maladaptive inflammatory response that fails to resolve. Two major features of this pathological scenario include macrophage (Mø) apoptosis and defective phagocytic clearance ("efferocytosis") of the dead Møs, which, in combination, lead to formation of the necrotic core. Necrotic cores promote plaque disruption, which in turn triggers acute atherothrombotic vascular events. With regard to advanced lesional Mø apoptosis, our studies have implicated a two-hit model involving endoplasmic reticulum (ER) stress and pattern recognition receptor (PRR) signaling. The ER stress hit is mediated in part by the transcription factor CHOP, which is abundantly expressed in vulnerable but not early-stage human coronary artery lesions. Using Western diet-fed Apoe-/- and Ldlr-/- mice, we showed that genetic deletion of CHOP decreases both Mø death and plaque necrosis in advanced aortic root plaques. Mechanistic studies revealed that CHOP promotes apoptosis by inducing ER oxidase 1α (ERO1α), which stimulates release of Ca2+ from ER stores via activation of IP3 receptors. The released Ca2+ activates Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is the key integrator of downstream apoptotic pathways in these cells. The PRR hit can be carried out by two receptor combinations: type A scavenger receptor (SRA)-Toll-like receptor 4 (TLR4) or CD36-TLR2. The latter can be activated by oxidized phospholipids (oxPLs) and oxidized LDL. Lipoprotein(a) [Lp(a)], a major carrier of oxPLs and a potent risk factor for coronary artery disease (CAD) in humans, can also trigger CD36-TLR2-mediated apoptosis in ER-stressed Mfs, suggesting a novel mechanism for the link between Lp(a) and CAD. With regard to efferocytosis, genetically altered mice were used to show a definitive role for the receptor MerTK in the uptake of apoptotic Møs in the atheromata of fat-fed Apoe-/- mice. Most importantly, there was a marked increase in plaque necrosis in the lesions of Mertk-/-;Apoe-/- vs. Apoe-/- mice. Additional data suggest that a defect in MerTK involving ADAM protease-mediated cleavage of the receptor is associated with vulnerable plaques in human arteries. In summary, there are two critical pathways that contribute to the failure of inflammation resolution in advanced atherosclerosis and thereby promote the progression of clinically dangerous atheromata: a detrimental Mø apoptosis pathway involving ER stress and PRR activation, the latter of which is a target of the human CAD risk factor Lp(a); and a protective efferocytosis pathway involving MerTK that may become dysfunctional in advanced lesions. Therapeutic targeting of these molecular processes through novel strategies designed to enhance inflammation resolution may lead to novel strategies to prevent acute coronary syndromes in subjects with pre-existing subclinical atherosclerosis.
Novel Mechanisms in the Resolution of Acute Inflammation
Charles N. Serhan, PhD, Harvard University, Brigham & Women's Hospital
Timely resolution of the acute inflammatory response provides new insights in host defense. Using a systems approach with self-limited inflammatory exudates to map tissue events, cell traffic and identification of proteinand chemical mediators, we identified new families of potent bioactive lipid-derived mediators, coined resolvinsand protectins in resolving exudates using lipid mediators lipidomics. Each of these pro-resolving mediators controls the duration and magnitude of acute inflammation in vivo with stereospecific sites of action in the picotonanogram range. The mapping of these endogenous resolution circuits provides new avenues to harness uncontrolled inflammation and consider the molecular basis of many inflammation-associated diseases (CSerhan American Journal of Pathology 2010). This presentation will provide an overview of our recent advances on the biosynthesis and functions of this novel genus of specialized pro-resolving mediators (SPM). These structurally distinct families of local chemical mediators were originally identified in murine exudates captured during the natural self-limited resolution phase and are also produced by human isolated cells. SPM include 3 families of chemical mediators resolvins, protectins and the most recent addition, maresins. These are biosynthesized from essential omega-3 fatty acids (EPA and DHA) and possess potent multi-pronged anti-inflammatory, pro-resolving and anti-microbial actions in murine models of sepsis (Spite et al Nature vol. 461,2009). The actions of SPM proved to be potent, cell type-specific and stereoselective with isolated human cells and in animal diseases. For example, they reduce pain and regulate miRNA identified that are of interest in resolution of acute inflammation. Together, these results indicate that natural resolution pathways may underlie many prevalent diseases associated with uncontrolled inflammation and open the potential for resolution-based pharmacology. The author acknowledges support of NIH grants DE019938, NS067686, and GM038765.
Endogenous Anti-Inflammation and Resolution: Players and Receptors
Mauro Perretti, PhD, Queen Mary University of London, UK
The process of acute inflammation relies on the active engagement of a series of pro-resolving mediators which assure temporal and spatial containment of the host reaction: a pro-inflammatory phase is followed by an anti-inflammatory and pro-resolving phase in line with "the beginning programmes the end" concept. Within the network of pro-resolving mediators is emerging a pattern of biological properties, shared by a variety of players, rendering specific actions paradigmatic (e.g. promotion of efferocytosis). Harnessing endogenous homeostatic pathways can lead to innovative anti-inflammatory therapeutics with beneficial applications for chronic inflammatory pathologies.
Within this area of investigation, Lipoxin A4 and Annexin A1 are two players able to halt leukocyte migration and promote macrophage phagocytosis of infective agents as well as apoptotic leukocytes. These effects are mediated by a specific receptor, the formyl peptide receptor type 2 (the acronym FPR2/ALX is currently used to identify the human receptor). Generation of a colony of mice deficient in the mouse orthologues of FPR2/ALX is helping elucidate the patho-physiological impact of this receptor (and its agonists) in acute inflammation providing, at the same time, proof-of-concept data for its exploitation in drug discovery programmes.
Resolvins and Protectins in Ocular Wound Healing, Inflammation and Angiogenesis
Karsten Gronert, PhD, UC Berkeley
The dynamic and temporally defined interplay of distinct populations of leukocytes is critical but a poorly defined feature of inflammatory events. By design inflammation is a frequent and self-resolving response that is essential for protection and integrity of all tissues. Successful execution of healthy inflammation depends on tightly regulated activation of leukocytes and their active resolution to return tissues to homeostasis. Dysregulation of this highly regulated process and stalled inflammation leads to PMN mediated tissue injury, activation of the inflammatory macrophage phenotype, transition to chronic inflammation and may promote/initiate adaptive immune responses. Hence, pathways that promote the resolution of PMN are of primary interest. Their function and regulation in the eye is just beginning to unfold and of considerable interest as the delicate visual axis has evolved a highly sophisticated intrinsic and protective lipid circuit. Our studies have identified a resident lipid circuit in the cornea that counter-regulates pro-inflammatory signals, promotes wound healing, controls pathological angiogenesis and regulates dynamic in vivo leukocyte behavior. The presentation is an update on current state of the field and new developments, which demonstrate that this intrinsic protective lipid circuit is regulated by dietary PUFA and exhibits sex-specific differences. Unraveling regulation of these intrinsic protective lipid circuits may provide insights into the etiology or pathogenesis of ocular inflammatory diseases.
From Bench to Clinic: Resolvins as New Therapeutics
Per Gjorstrup, MD, PhD, Resolvyx Pharmaceuticals
Existing preclinical data now indicate that resolvins and protectins, either as their natural endogenous mediators, or as synthetic analogs, present a huge potential as a novel treatment approach for chronic inflammatory disease. With resolvins being first-in-class lead compounds several requirements had to be met in the selection of a proof-of-concept indication, not least due to the complex and redundant pathologies commonly seen in inflammatory disease. The choice was made to develop a first drug candidate for the treatment of dry eye disease. Dry eye is an inflammatory condition provoked by environmental stresses due to loss of the protective tear film. It involves activation of both innate and in severe cases the adaptive immune systems, as well as epithelial activation with release of proinflammatory mediators. The opportunity to investigate all these aspects of inflammation in an approach using murine models of eye inflammation combined with investigations of inflammatory mediator release and tissue survival using human corneal cells, created a unique drug development opportunity. The easy access to eye tissue allowed the direct assessment of dose required to achieve therapeutic drug concentrations in the relevant target tissue, and together with in vivo and in vitro pharmacological data supported the development of an algorithm to select doses for the first successful human clinical phase 2 study based on the resolvin concept, and will be presented. The relevance of this approach for dose selection when moving a systemically delivered resolvin into phase 2 clinical studies will also be discussed.
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