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Fibrosis: Therapeutic Target or Inevitable Outcome?

Fibrosis: Therapeutic Target or Inevitable Outcome?

Tuesday, October 22, 2013

The New York Academy of Sciences

Presented By

 

Fibrosis is a common feature of chronic organ injury and leads to progressive life-threatening diseases. Fibrotic diseases of different organs (kidney, heart, lung, and liver) represent increasingly high unmet medical need. Mechanisms currently under evaluation as anti-fibrotic therapies include targeting inflammation, growth factors, epigenetics, and collagen biogenesis. Despite experimental successes, anti-fibrotic drug development is challenging, and so far unsuccessful. This invites the questions: is fibrosis a potent contributor to disease progression or an adaptive mechanism; can the fibrotic process be stopped, or more ideally, reversed? Is prevention the key, or are alternative strategies that aim to target regenerative approaches and restore the balance between structure and function viable? Does the fibrotic process have organ specific components or we are facing a common enemy? For future success anti-fibrotic strategies will have to develop new paradigms to overcome the limitations which hinder the development of effective therapies.

The prolonged natural history of the disease, the complex interaction between dynamically transforming cell populations, and the currently used endpoints are difficult to capture within the time and economic constraints of most clinical trials. Today it is increasingly possible to discover and validate novel molecules or pathways involved in fibrogenesis by employing diverse animal models and new genetic technologies. There have also been significant technical advancements in the area of noninvasive fibrosis assessment that may change the black box nature of the currently used clinical development endpoints. This symposium will review the mechanistic link between fibrosis and disease and explore ways to use biomarkers and imaging to translate laboratory results into clinical success.

Registration and Webinar Pricing

Member$30
Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45


The Biochemical Pharmacology Discussion Group is proudly supported by




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

Agenda

* Presentation titles and times are subject to change.


Tuesday, October 22, 2013

8:15 AM

Registration and continental breakfast

8:45 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Scott MacDonnell, PhD, Boehringer-Ingelheim Pharmaceuticals

9:00 AM

Thrombin: A Potential Therapeutic Target for Scleroderma Interstitial Lung Disease
Richard M. Silver, MD, Medical University of South Carolina

9:40 AM

Organ Fibrosis: Mechanism and Molecular Connection to Cancer
Raghu Kalluri, MD, PhD, The University of Texas MD Anderson Cancer Center

10:20 AM

Coffee break

10:50 AM

Pericytes in Driving Multiple Organ Fibrosis
Jeremy S. Duffield, MD, PhD, University of Washington

11:30 AM

The Role of Epithelial Cells and New Epithelial Targets for Fibrosis Treatment
Marco Prunotto, PhD, Hoffmann-La Roche

12:10 PM

Lunch break

1:10 PM

Translational Value of the Bleomycin Rat Model for the Treatment of Patients with Idiopathic Pulmonary Fibrosis (IPF)
Yasmina Bauer, PhD, Actelion Pharmaceuticals Ltd

1:50 PM

ECM and Related Molecules as Biomarkers for Patients with Idiopathic Pulmonary Fibrosis
Eric S. White, MD, University of Michigan Medical School

2:30 PM

Coffee break

3:00 PM

Energy Sensing and Renal Fibrosis
Kumar Sharma, MD, University of California, San Diego

3:40 PM

Important Role of mTORC2-mediated Sustained PKC Activation in Fibroblast Migration and Pulmonary Fibrosis
Dan Wu, PhD, Yale University

4:20 PM

Panel Discussion: 'Similarities and Differences Between the Mechanisms of Fibrosis Across Different Organs'
All speakers, moderated by Scott MacDonnell, PhD, Boehringer-Ingelheim Pharmaceuticals

5:00 PM

Closing remarks: Katalin Kauser, MD, PhD, DSc

Networking reception

6:00 PM

Close

Speakers

Organizers

Katalin Kauser, MD, PhD, DSc

Bayer Healthcare

Dr. Katalin Kauser is currently Vice President at Bayer HealthCare Ltd. heading the Hematology Research Department in Mission Bay, San Francisco, California. Prior to joining Bayer she was Vice President at Actelion Pharmaceuticals, Ltd. leading the Cardiovascular Pharmacology Department in Allschwill, Switzerland. She also held positions at Boehringer-Ingelheim Pharmaceutical Inc., Ridgefield, Connecticut, as a Director of the Cardiovascular Research Department, and leading the worldwide collaborative preclinical research activities for BI's marketed angiotensin receptor inhibitor, Micardis.

Prior to moving to the East Coast, Dr. Kauser was a Scientific Unit Head in Gene Therapy Research, and the Head of the Regenerative Research Unit at the Cardiovascular Department at Berlex Biosciences, Richmond, California. Dr. Kauser is a graduate of Semmelweis Medical University, Budapest, Hungary, and a post-doctoral fellow of the Medical College of Wisconsin, Milwaukee, Wisconsin. Throughout her carrier she has been interested in the pathophysiology of cardiovascular remodeling, the balance between fibrotic changes and regenerative mechanisms, and the understanding of the importance and 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. Her research has contributed to the understanding of gender differences in endothelial function, cardiovascular protection by steroid hormones, and to new strategies towards novel cardiovascular therapeutic approaches including gene therapy and cell therapy using adult bone marrow derived progenitor cells.

In 2007 Dr. Kauser co-edited a volume of the book series Handbook of Experimental Pharmacology, entitled Bone Marrow-Derived Progenitors. In addition to her MD degree in 1986, Dr. Kauser received her PhD degree in Physiology in 1991, and a Doctor of Science degree in 2005 from the Hungarian Academy of Science.

Scott MacDonnell, PhD

Boehringer-Ingelheim Pharmaceuticals

Dr. 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 in Philadelphia, PA. He completed a post-doctoral 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 recognized as a best manuscript by the editorial board in 2010. Additionally, Scott was recognized by the International Society for Heart Research and awarded the young investigator of the year in 2008. Scott currently works as a principal scientist at Boehringer Ingelheim within the department of CardioMetabolic Disease Research. His research is focused on identifying novel therapeutic treatment options for chronic kidney disease, heart failure, and fibrosis.

Silvia Pomposiello, PhD

F. Hoffmann-La Roche

Carolyn Foster, PhD

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Yasmina Bauer, PhD

Actelion Pharmaceuticals Ltd

Yasmina Bauer graduated from the University of Brittany (France) with a major in molecular microbiology and completed her master degree in the Biotechnology Research Institute of Novartis, Research Triangle Park, North Carolina (USA). During her PhD she discovered novel mechanisms of polarized growth in the lab of Prof. Peter Philippsen at the Biocenter Basel (Switzerland), using genomics and cell biology tools. Following a postdoctoral position at the Biocenter / Basel (Switzerland), she joined the biotechnology company Morphochem (Basel, Switzerland), where she established a DNA microarray facility for chemical genomics. In 2004 she joined Actelion Pharmaceuticals (Allschwil, Switzerland) as a lab head in the drug discovery department. She established a genomics core unit dedicated to pharmacogenomics and toxicogenomics. Today her work is focused on biomarker discovery using genomics and systems biology tools. Over the past years she has worked on the discovery and characterization of biomarkers related to Lung disease, Cardiovascular Disease & Fibrosis.

Jeremy S. Duffield, MD, PhD

University of Washington

Jeremy is a Physician Scientist who graduated from Oxford and Edinburgh Universities, UK. After setting up his own lab as Assistant Professor of Medicine at Harvard Medical School he moved to University of Washington, Seattle as Associate Professor of Medicine & Pathology and established NIDDK Investigator at the Institute of Stem Cell & Regenerative Medicine, and 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, monocytes, in injury and repair and on the role of pericytes in microvascular remodeling and fibrosis.

Dr. Duffield is a recipient of the Young Investigator Award from the British Renal Association (2001) and Medical Research Society (2002), NIDDK Young Investigator/Scholar Award (2010) and the American Society of Nephrology Young Investigator Award 2013. In 2011 he became an elected member of the American Society for Clinical Investigation. He also serves on scientific study sections at the NIDDK/NHLBI and the Scientific Advisory Boards of Promedior Inc. and Regulus Therapeutics; companies dedicated to the development of anti-fibrotic therapies. He practices Nephrology part-time at University of Washington Medical Center with special interests in Systemic Lupus Erythematosis, Systemic Vasculitis and Pregnancy related kidney disorders. In his 'spare' time he races bicycles, climbs mountains, skis, plays tennis, grows organic vegetables, looks after children (his own) and fixes things that are broken.

Raghu Kalluri, MD, PhD

The University of Texas MD Anderson Cancer Center

Marco Prunotto, PhD

F. Hoffmann-La Roche

Kumar Sharma, MD

University of California, San Diego

Dr. Sharma is the Director of the Center for Renal Translational Medicine and Institute for Metabolomic Medicine and Professor of Medicine at UCSD in San Diego. Dr. Sharma has had a dedicated and consistent translational approach for diabetic complications for the past 15 years and has expertise in developing phenotype analysis using imaging, molecular and biochemical methods, genomics, microarray, proteomics and metabolomics. His group has had numerous studies linking clinical phenotypes of patients with genomics and biomarkers. His recent studies have employed novel imaging and systems biology approaches to understand novel mechanisms related to obesity-related complications, diabetic kidney disease and novel therapies.

His work has had a major impact in the field with respect to novel anti-fibrotic therapies for chronic kidney disease and his group has recently completed a multi-center NIH funded clinical trial with an oral anti-fibrotic agent. His major focus in the past few years has been to develop novel biomarkers for chronic kidney disease and diabetic complications with major new funding from the NIH. In particular, recent metabolomic studies in humans have led to novel 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

Dr. Richard 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. Dr. 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 Adult Rheumatology at the University of California at San Diego. Dr. Silver joined the MUSC faculty in 1981, where currently he is 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

Eric S. White, MD is Associate Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at the University of Michigan Medical School. Dr. 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. Dr. 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, PhD

Yale University

Dr. Dianqing (Dan) Wu is currently a Professor at the Department of Pharmacology, Yale University School of Medicine. He is also a member of the Vascular Biology and Therapeutics Program, Yale Cancer Center, and Yale Stem Cell Center. He got his BS in Nanjing University, China, in 1985 and his PhD with Dr. Gordon Sato at Clarkson University-W. Alton Jones Cell Science Center, New York, in 1991. He received his postdoctoral training with Dr. Melvin I. Simon at Caltech between 1991 and 1994. He started his independent research career as an assistant professor at the University of Rochester in 1994 and was promoted to associate professor in 1998. He relocated to the University of Connecticut Health Center in 2000 and was promoted to professor in 2004. In 2006, he 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. He will present the recent progress in his laboratory on the characterization of a novel mTORC2-mediated persistent PKC activation mechanism that is important for fibroblast migration and lung fibrosis development.

Sponsors

Bronze Sponsor

F. Hoffmann-La Roche

Academy Friends

Bayer HealthCare

DiscoveRx

Promotional Partners

American Lung Association

American Thoracic Society

Cystic Fibrosis Foundation

Nature

Pulmonary Fibrosis Foundation

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

Abstracts

Thrombin: A Potential Therapeutic Target for Scleroderma Interstitial Lung Disease
Richard M. Silver, Medical University of South Carolina

Systemic sclerosis (scleroderma, SSc) is a multisystem autoimmune connective tissue disease of unknown etiology. Scleroderma-associated interstitial lung disease (SSc-ILD) is a frequent complication and a leading cause of death. We identified thrombin as a potential mediator of SSc-ILD and have demonstrated in vitro and in an animal model that blocking thrombin with the direct thrombin inhibitor dabigatran etexilate has anti-fibrotic effects. Dabigatran prevents thrombin-induced apoptosis of alveolar epithelial cells while simultaneously diminishing lung myofibroblast resistance to apoptosis. In the murine model of bleomycin-induced lung fibrosis, the anti-fibrotic effects of dabigatran etexilate were seen at concentrations that did not cause significant bleeding or coagulation effects. We conclude that thrombin may be a key mediator of the "apoptosis paradox" and that dabigatran etexilate warrants further study for the treatment of SSc-ILD.
 

Pericytes in Driving Multiple Organ Fibrosis
Jeremy S. Duffield, University of Washington

Fibrosis and the process of making pathological matrix, known as fibrogenesis, are widespread in chronic diseases of almost all organs in the body. Recent studies from disparate investigations have identified discrete perivascular cells, attached to capillaries as major precursors of fibrogenic cells. These perivascular cells are not only fibrogenic cells but serve as sentinels of the inflammatory response. In this presentation we will review the evidence for a widespread role of perivascular cells in fibrogenesis and explore mechanisms by which cells which normally regulate vascular homeostasis differatiate into matrix forming cells.
 

Translational Value of the Bleomycin Rat Model for the Treatment of Patients with Idiopathic Pulmonary Fibrosis (IPF)
Yasmina Bauer, Actelion Pharmaceuticals Ltd

Intratracheal (i.t.) application of bleomycin is known to induce inflammatory and fibrotic reactions within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Although these features are reminiscent to those found in IPF patients, the bleomycin animal model is not representing the chronic and progressive nature of human IPF. A better understanding of this animal model and its relevance to human IPF on a molecular level is key to evaluate novel compounds with disease modifying potential. Animal model expression data from a time course experiment was thus compared with whole genome expression data from IPF patient lung biopsies.
 
The temporal development of gene expression signatures was then investigated. A pronounced inflammatory response was detected at day 3, which was followed by a transient fibrogenic phase with peak signatures at week 2. Beyond week 2, the pro-fibrotic signatures decreased and only a few genes remained differentially expressed. The best correlation of gene expression signatures between human IPF and the bleomycin-induced lung fibrosis model was observed in animals 1 week after bleomycin instillation. Furthermore, several disease-relevant translational markers were identified and these might offer new possibilities to evaluate efficacy of novel therapeutic concepts in this preclinical model and human clinical trials.
 

ECM and Related Molecules as Biomarkers for Patients with Idiopathic Pulmonary Fibrosis
Eric S. White, University of Michigan Medical School

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder of lung scarring with no clear etiology and currently no effective therapeutic agents. The natural history of IPF is unclear; while many patients decline slowly and progressively, others have acute declines in lung function that are difficult to predict. Currently, there are no biomarkers to assist with diagnosis or prognosis of patients with IPF, although preliminary studies suggest that markers of extracellular matrix (ECM) turnover and related molecules may provide important information in this, and other, fibrotic disorders. This talk with highlight work ongoing in our lab evaluating the role of ECM and related molecules as biomarkers in fibrotic diseases.
 

Energy Sensing and Renal Fibrosis
Kumar Sharma, MD, University of California, San Diego

The kidney has robust and early inflammatory changes in response to challenges in caloric balance, from high fat feeding or with diabetes. Progressive accumulation of matrix molecules, largely driven by TGF-b, leads to ultimate organ dysfunction and renal failure. The global epidemic of obesity and diabetes likely is a major contributor to the worldwide increase in end-stage renal disease. Recent studies have identified that the master energy sensing enzyme, AMPK is highly active in the normal kidney and is inhibited with high fat feeding and diabetes in mouse models. A consequence of AMPK inhibition is an increase in inflammation and fibrosis mediated in part by NAPDH oxidases and TGF-b. Recent clinical studies with urine metabolomics indicates that mitochondrial function is markedly reduced in patients with diabetic kidney disease. Novel imaging studies in animal models of diabetes demonstrated that mitochondrial superoxide production and mitochondrial biogenesis was reduced with diabetes and stimulation with AMPK increases mitochondrial superoxide production and improves parameters of diabetic kidney disease. These studies indicate that reduced AMPK plays a critical role in the early response of the kidney to states of caloric imbalance. A strategy to stimulate mitochondrial function and biogenesis would be beneficial in reducing inflammation, fibrosis and possibly, enhancing organ regeneration.
 

Important Role of mTORC2-mediated Sustained PKC Activation in Fibroblast Migration and Pulmonary Fibrosis
Dianqing (Dan) Wu, Yale University School of Medicine

Cell migration is a fundamental biological process that plays an important role in a wide range of biological and physiological processes. Its deregulation causes or contributes to many diseases, including fibrosis. The migratory kinetics of fibroblast cells suggest a possible requirement of sustained signaling events, in addition to the acute ones, to support their migration. We recently identified one of the sustained signaling pathways as being critically important for LPA-induced fibroblast migration. In this pathway, LPA acts, through a Gα12-ARAF-ERK pathway, to transcriptionally upregulate the expression of an ubiquitin E3 ligase RFFL, which polyubiquitinates and destabilizes an mTORC2 (Mammalian target of rapamycin complex 2) component, PRR5L. In the presence of PRR5L, mTORC2 does not phosphorylate PKC at its HM site. Thus, the elimination of PRRL5L by RFFL leads to sustained PKC HM phosphorylation and activation. This pathway is not only important for fibroblast migration in vitro, also has a key role in pulmonary fibrosis development in a mouse model. Therefore, our results reveal a novel, transcription-based sustained signaling mechanism that is important for fibroblast migration and pulmonary fibrosis development.
 

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