eBriefing

Fibrosis: Therapeutic Target or Inevitable Outcome?

Fibrosis
Reported by
Alla Katsnelson

Posted January 28, 2014

Overview

On October 22, 2013, scientists convened at the New York Academy of Sciences for a symposium titled Fibrosis: Therapeutic Target or Inevitable Outcome? It provided an opportunity for researchers in academia and the pharmaceutical industry to discuss gaps in our knowledge of the underlying biology of different fibrotic diseases, as well as challenges and promising strategies in drug development. As a condition occurring in many different organ systems and implicated in a variety of diseases, fibrosis represents an area of significant unmet medical need. Most of the talks focused on kidney or lung fibrosis, and researchers grappled with the difficulties posed by problematic animal models and the heterogeneity of patient populations affected by fibrosis. The symposium was presented by the Academy's Biochemical Pharmacology Discussion Group.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Jeremy S. Duffield, MD, PhD (University of Washington)
Scott MacDonnell, PhD (Boehringer Ingelheim Pharmaceuticals)
Marco Prunotto, PhD (F. Hoffmann-La Roche)
Kumar Sharma, MD (University of California, San Diego)
Richard M. Silver, MD (Medical University of South Carolina)
Dianqing (Dan) Wu, PhD (Yale University)


The Biochemical Pharmacology Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Journal Articles and Websites

Yasmina Bauer

Arrowsmith J. A decade of change. Nat Rev Drug Discov. 2012;11(1):17-8.

Moeller A, Ask K, Warburton D, et al. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol. 2008;40(3):362-82.

Lung Tissue Research Consortium

Jeremy S. Duffield

Alon R, Nourshargh S. Learning in motion: pericytes instruct migrating innate leukocytes. Nat Immunol. 2013;14(1):14-5.

Dulauroy S, Di Carlo SE, Langa F, et al. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med. 2012;18(8):1262-70.

Göritz C, Dias DO, Tomilin N, et al. A pericyte origin of spinal cord scar tissue. Science. 2011;333(6039):238-42.

Humphreys BD, Lin SL, Kobayashi A, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176(1):85-97.

Hung C, Linn G, Chow YH, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188(7):820-30.

Raghu Kalluri

LeBleu VS, Taduri G, O'Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19(8):1047-53.

Marco Prunotto

Koesters R, Kaissling B, Lehir M, et al. Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol. 2010;177(2):632-43.

Moll S, Ebeling M, Weibel F, et al. Epithelial cells as active player in fibrosis: findings from an in vitro model. PLoS One. 2013;8(2):e56575.

Palmer SC, Sciancalepore M, Strippoli GF. Trial quality in nephrology: how are we measuring up? Am J Kidney Dis. 2011;58(3):335-7.

Sharma K, Ix JH, Mathew AV, Cho M, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011;22(6):1144-51.

Kumar Sharma

Fink B, Laude K, McCann L, et al. Detection of intracellular superoxide formation in endothelial cells and intact tissues using dihydroethidium and an HPLC-based assay. Am J Physiol Cell Physiol. 2004;287(4):C895-902.

Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes. 2009;58(7):1651-8.

Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology. 2006;21:48-60.

Hardie DG. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 2008;582(1):81-9.

Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106(21):8665-70.

Schulz TJ, Zarse K, Voigt A, et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007;6(4):280-93.

Zou MH, Wu Y. AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function. Clin Exp Pharmacol Physiol. 2008;35(5-6):535-45.

Richard M. Silver

Bogatkevich GS, Tourkina E, Silver RM, Ludwicka-Bradley A. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J Biol Chem. 2001;246:45184-92.

Bogatkevich GS, Gustilo E, Oates JC, et al. Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts. Am J Physiol Lung Cell Mol Physiol. 2005;288:L190-L201.

Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum. 2009;60:3455-64.

Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis. Ann Rheym Dis. 2007;66(7):940-4.

Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:350-6.

Eric S. White

American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165(2):277-304.
This joint statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) was adopted by the ATS board of directors and by the ERS Executive Committee in June 2001.

Booth AJ, Hadley R, Cornett AM, et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med. 2012;186(9):866-76.

Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med. 2013;5(205):205ra136.

Lijnen PJ, Maharani T, Finahari N, Prihadi JS. Serum collagen markers and heart failure. Cardiovasc Hematol Disord Drug Targets. 2012;12(1):51-5.

McDonald EA, Friedman JF, Sharma S, et al. Schistosoma japonicum soluble egg antigens attenuate invasion in a first trimester human placental trophoblast model. PLoS Negl Trop Dis. 2013;7(6):e2253.

Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.

White ES, Lazar MH, Thannickal VJ. Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis. J Pathol. 2003;201(3):343-54.

Dan Wu

Gan X, Wang J, Su B, Wu D. Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 2011;286(13):10998-1002.

Gan X, Wang J, Wang C, et al. PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat Cell Biol. 2012;14(7):686-96.

Gan X, Wang C, Patel M, et al. Different Raf protein kinases mediate different signaling pathways to stimulate E3 ligase RFFL gene expression in cell migration regulation. J Biol Chem. 2013;288(47):33978-84.

Organizers

Katalin Kauser, MD, PhD, DSc

Bayer HealthCare
publications

Katalin Kauser is vice president at Bayer HealthCare, heading the Hematology Research Department. Before joining Bayer she was vice president at Actelion Pharmaceuticals, leading the Cardiovascular Pharmacology Department. She also held positions at Boehringer Ingelheim and Berlex Biosciences. Kauser is a graduate of Semmelweis Medical University, Hungary, and completed a postdoctoral fellowship at the Medical College of Wisconsin. In addition to her MD, she also holds a PhD in physiology, and a Doctor of Science from the Hungarian Academy of Science. Kauser is interested in the pathophysiology of cardiovascular remodeling, the balance between fibrotic changes and regenerative mechanisms, and the cross-talk between structural and functional components of the cardiovascular system. She has been recognized for her research in vascular biology, especially in the field of endothelial dysfunction and endothelial nitric oxide synthase regulation bridging from physiology to regenerative medicine applications.

Scott MacDonnell, PhD

Boehringer Ingelheim Pharmaceuticals
publications

Scott MacDonnell obtained his undergraduate and Master's degrees in exercise physiology from the University of Delaware and completed his doctoral work in cardiovascular physiology at Temple University. He completed a postdoctoral fellowship at Temple University Medical School in the lab of Dr. Steve Houser. His fellowship research focused on identifying mechanisms responsible for the pathogenesis of heart failure. Specifically, his work examined the role of CaMKII in altered contractility, myocytes apoptosis, and transcriptional regulation associated with heart failure progression. This work has been published in Circulation Research and was recognized as a Best Manuscript by the editorial board in 2010. MacDonnell has also been recognized by the International Society for Heart Research and awarded the Young Investigator of the Year in 2008. MacDonnell is a principal scientist at Boehringer Ingelheim in the Department of CardioMetabolic Disease Research. He is focused on identifying novel therapeutic treatment options for chronic kidney disease, heart failure, and fibrosis.

Silvia Pomposiello, PhD

F. Hoffmann-La Roche
publications

Carolyn Foster, PhD

Jennifer Henry, PhD

The New York Academy of Sciences


Speakers

Yasmina Bauer, PhD

Actelion Pharmaceuticals Ltd.
publications

Yasmina Bauer graduated from the University of Brittany, France, with a major in molecular microbiology and completed her Master's degree at the Biotechnology Research Institute of Novartis. During her PhD she discovered novel mechanisms of polarized growth in the lab of Prof. Peter Philippsen at the Biocenter in Basel, Switzerland, using genomics and cell biology tools. Following a postdoctoral position at the Biocenter, she joined the biotechnology company Morphochem, where she established a DNA microarray facility for chemical genomics. She joined Actelion Pharmaceuticals in 2004 as a lab head in the Drug Discovery Department. She established a genomics core unit dedicated to pharmacogenomics and toxicogenomics. Her work is focused on biomarker discovery using genomics and systems biology tools. She has worked on the discovery and characterization of biomarkers related to lung disease, cardiovascular disease, and fibrosis.

Jeremy S. Duffield, MD, PhD

University of Washington
website | publications

Jeremy S. Duffield is a physician scientist who graduated from Oxford University and Edinburgh University in the UK. After setting up his own lab as an assistant professor of medicine at Harvard Medical School he moved to the University of Washington, where he is an associate professor of medicine and pathology and an established NIDDK investigator at the Institute of Stem Cell & Regenerative Medicine and the Center for Lung Biology. He is also a member the Kidney Research Institute. His laboratory is focused on the role of innate immune response cells and monocytes in injury and repair and on the role of pericytes in microvascular remodeling and fibrosis. Duffield is a recipient of Young Investigator Awards from the British Renal Association and the Medical Research Society, of an NIDDK Young Investigator/Scholar Award, and of the American Society of Nephrology Young Investigator Award. He practices nephrology part-time at the University of Washington Medical Center, with special interests in systemic lupus erythematosis, systemic vasculitis, and pregnancy-related kidney disorders.

Raghu Kalluri, MD, PhD

The University of Texas MD Anderson Cancer Center
website | publications

Raghu Kalluri is a professor in the Department of Cancer Biology at the University of Texas MD Anderson Cancer Center. He focuses on cancer biology and clinical and translational sciences. He holds a PhD from the University of Kansas Medical Center and an MD from Brown University School of Medicine.

Marco Prunotto, PhD

F. Hoffmann-La Roche
publications

Kumar Sharma, MD

University of California, San Diego
website | publications

Kumar Sharma is the director of Translational Research in Kidney Disease and a professor of medicine at the University of California, San Diego. Sharma takes a translational approach to diabetic complications and has expertise in developing phenotype analysis using imaging, molecular, and biochemical tools, genomics, microarray, proteomics, and metabolomics. His group has linked clinical phenotypes of patients with genomics and biomarkers. His recent studies have employed novel imaging and systems biology approaches to understand mechanisms of obesity-related complications and diabetic kidney disease. His work has elucidated anti-fibrotic therapies for chronic kidney disease and his group has recently completed a multi-center National Institutes of Health-funded clinical trial with an oral anti-fibrotic agent. He is currently focused on developing biomarkers for chronic kidney disease and diabetic complications with new funding from the NIH. In particular, recent metabolomic studies in humans have led to insights into the pathogenesis of diabetic complications and the role of the kidney in energy metabolism.

Richard M. Silver, MD

Medical University of South Carolina
website | publications

Richard M. Silver is the director of the Division of Rheumatology & Immunology at the Medical University of South Carolina. He is a graduate of the University of Tennessee and Vanderbilt University School of Medicine. Silver completed training in internal medicine at the University of North Carolina at Chapel Hill. He trained in pediatric rheumatology at London's Northwick Park Hospital and in adult rheumatology at the University of California, San Diego. Silver joined the MUSC faculty in 1981, where he is a professor of medicine and pediatrics. In 2007, MUSC's Board of Trustees named him a Master Teacher and bestowed the University's highest academic recognition, Distinguished University Professor. He was named Doctor of the Year in 2007 by the Scleroderma Foundation. His major clinical and research interests are systemic sclerosis and interstitial lung disease.

Eric S. White, MD

University of Michigan Medical School
website | publications

Eric S. White is an associate professor of medicine in the Division of Pulmonary and Critical Care Medicine at the University of Michigan Medical School. White's clinical focus is on patients with interstitial lung diseases, such as IPF, sarcoidosis, and connective tissue disease-associated interstitial lung disease. His lab studies fibroblast biology and the basic underpinnings of fibrotic lung disease, mechanisms of lung regeneration, and biomarkers in interstitial lung disease and other fibrotic disorders. White is funded by the National Institutes of Health, the Drews Sarcoidosis Research Fund at the University of Michigan, and the Quest for Breath/Martin Edward Galvin Fund for Pulmonary Fibrosis Research at the University of Michigan.

Dianqing (Dan) Wu

Yale University
website | publications

Dan Wu is a professor in the Department of Pharmacology at Yale University School of Medicine. He is also a member of the Vascular Biology and Therapeutics Program at Yale Cancer Center and of Yale Stem Cell Center. He received his PhD working with Dr. Gordon Sato at Clarkson University's W. Alton Jones Cell Science Center and completed postdoctoral training with Dr. Melvin I. Simon at California Institute of Technology. He started his independent research career at the University of Rochester, relocated to the University of Connecticut Health Center, and then moved to his current position at Yale Medical School. His research interests focus on signaling mechanisms for Wnt and chemoattractants and their functions in a broad range of biological and pathophysiological processes. His laboratory is working on the characterization of a novel mTORC2-mediated persistent PKC activation mechanism that is important for fibroblast migration and lung fibrosis development.


Alla Katsnelson

Alla Katsnelson is a freelance science writer and editor, specializing in health, biomedical research, and policy. She has a doctorate in developmental neuroscience from Oxford University and a certificate in science communication from the University of California, Santa Cruz, and writes regularly for scientists and non-scientists alike.

Sponsors

Bronze Sponsor

F. Hoffmann-La Roche

Academy Friends

Bayer HealthCare

DiscoveRx

This symposium has been endorsed by the American Thoracic Society.

The Biochemical Pharmacology Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer