Bryan Copple, Ph.D.

  • Drug Discovery and Receptor Faculty, Hepatic Faculty

Pharmacology & Toxicology
Associate Professor
B403 Life Sciences
1355 Bogue Street
East Lansing, MI 48824
Email: copple@msu.edu
Phone: 517-884-6691
Fax: 517-353-8915

Fields of Interest: The research in my laboratory is focused on understanding the role of the immune system and hypoxia in the development of liver disease.

Bryan Copple on MSU Scholars

Educational Background

  • 1988-1991 - B.S., Biology, Morningside College, Iowa
  • 1991-1997 - Ph.D., Pharmacology, University of Nebraska Medical Center
  • 1997-1998 - Research Associate, Pharmacology & Toxicology, Michigan State University
  • 1998-1999 - Research Associate, Multidisciplinary Training in Environmental Toxicology, Michigan State University
  • 1999-2001 - NRSA Postdoctoral Fellow, Pharmacology & Toxicology, Michigan State University
  • 2001-2003 - Research Associate, Pharmacology & Toxicology, Michigan State University
  • 2003-2010 - Assistant Professor, Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center
  • 2010-2011 - Associate Professor, Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center
  • 2011-present - Associate Professor, Pharmacology & Toxicology, Michigan State University

Biography & Current Research

Research Synopsis

Regulation of Inflammation in the Liver by Early Growth Response Factor-1

Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This results in the accumulation of bile acids in the liver, hepatic inflammation, hepatocyte injury, and under chronic conditions, hepatic fibrosis. The pathogenesis of hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. Interestingly, inflammation associated with cholestasis occurs independently of tumor necrosis factor-? and interleukin-1, suggesting that this process is regulated by a novel, previously undescribed mechanism. Therefore, the overall goal of our research is to elucidate the mechanism by which cholestasis causes inflammation in the liver. Our studies indicate that the transcription factor, early growth response factor-1 (Egr-1), is critical for this process. Egr-1 is rapidly upregulated in hepatocytes during cholestasis. Upregulation of Egr-1 appears to be mediated directly by bile acids, since exposure of primary mouse hepatocytes to pathological concentrations of bile acids upregulates Egr-1. Our studies show further that upregulation of macrophage inflammatory protein-2, intercellular adhesion molecule-1, neutrophil accumulation, and hepatocyte injury are dramatically reduced in Egr-1 knockout mice with cholestasis. These results suggest that upregulation of Egr-1 in hepatocytes is vital for the development of neutrophil-dependent inflammatory liver injury, and as such, is a novel mechanism of inflammation in the liver. Furthermore, these studies indicate that Egr-1 provides the critical link between elevated concentrations of bile acids that occur during cholestasis and the production of proinflammatory mediators in liver. Elucidation of the molecular mechanism by which Egr-1 regulates inflammation would provide important insight into whether development of therapeutics that target Egr-1 would be effective for the treatment of hepatocyte injury in patients with cholestasis.

Role of Hypoxia-inducible Factors in the Development of Liver Fibrosis

Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. Our studies have investigated the hypothesis that the transcription factor, hypoxia-inducible factor-1? (HIF-1?), is activated in the liver during chronic injury and regulates expression of profibrotic proteins. Hypoxia-inducible factors (HIFs) are a group of transcription factors that are rapidly activated in cells exposed to hypoxia. Once activated, these transcription factors translocate to the nucleus and regulate expression of genes involved in glycolysis, cell survival, proliferation, erythropoiesis and angiogenesis. To investigate the hypothesis that HIFs are important for fibrosis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1? protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1? is required for the development of fibrosis, Control and HIF-1?-deficient mice were subjected to BDL. Levels of type I collagen and ?-smooth muscle actin mRNA and protein were increased in Control mice by 14 days after BDL. These levels were significantly reduced in HIF-1?-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1? promoted liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, fibroblast growth factor-2, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in Control mice subjected to BDL when compared to HIF-1?-deficient mice. Our studies demonstrate that HIF-1? is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

Awards & Achievements

Awards

Morningside College

  • Zeta Sigma Scholastic Honor Society, 1991
  • Graduated Magna Cum Laude, 1991

University of Nebraska Medical Center

  • University of Nebraska Medical Center Regents Tuition Fellowship, 1992-96
  • Pharmaceutical Sciences Training Program Travel Award, 1993
  • Herbert L. Davis Scholarship in Pharmacology, 1994 (awarded for the best Pharmacology Graduate Student oral presentation at the Annual Student Research Forum at the University of Nebraska Medical Center)
  • Thomas Jefferson Ingenuity Award, 1997 (awarded to the top graduating Graduate Student at the University of Nebraska Medical Center)

University of Kansas Medical Center

  • Travel Award, 2006, 2008, 2009
  • Thomas G. Noffsinger, Ph.D. Investigator Award, 2006
  • Kansas IDeA network of Biomedical Research Excellence Faculty Scholar Award, 2008

Michigan State University

  • Postdoctoral Fellowship, Multidisciplinary Training in Environmental Toxicology Training Grant, 1998-99
  • NIH Individual National Research Service Award, Pharmacology and Toxicology, 1999-2001

Achievements

  • Presidential Poster of Distinction, American Association for the Study of Liver Disease Annual Meeting, Boston, MA, 2006, 2009
  • Discussion Panel entitled “Mentoring Teams: Guides, Allies, and Advocates,” Educator Series, Office of Professional Development and Academic Affairs at the University of Kansas Medical Center, 2007
  • Served as Secretary for the University of Kansas Medical Center Chapter of Sigma Xi, 2006-08
  • Served as the President-Elect for the University of Kansas Medical Center, Chapter of Sigma Xi, 2008-09

Committees & Activities

Committees

University of Kansas Medical Center

  • Pharmacology, Toxicology, and Therapeutics, Web-site Committee, 2005
  • Pharmacology, Toxicology, and Therapeutics, Student Expectations Committee, 2005
  • Pharmacology, Toxicology, and Therapeutics, Summer Anything Goes Seminar series, Chair, 2006
  • Pharmacology, Toxicology, and Therapeutics, COBRE Histology Core Facility Director, 2007-2011
  • Member, Internal Advisory Board for the University of Kansas Medical Center Liver Center, 2007-2011
  • Representative for the Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine Faculty Council, 2009-2011

Editorial Boards

  • Liver International (official journal of the International Association for the Study of the Liver)

National & International Society Committees

  • Ad hoc Review Group, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2009

Society of Toxicology

  • Member, Discussion Panel, “Career Resource and Development Seminar: Life After Your Post-doc: Advice on Finding and Landing a Job,” 2006 Annual Meeting, San Diego, CA
  • Academic Advisor Facilitator, Undergraduate Education Program, What is Graduate School and What Can I Expect, 2010, Salt Lake City

Central States Toxicology Annual Meeting (Chapter of the Society of Toxicology)

  • Poster Presentation Judge, University of Iowa, Iowa City, IA, 2007-2009
  • Secretary/Treasurer, 2008-present

Other Activities

Book Reviewer
  • Phillips MI, “Methods in Molecular Medicine: Antisense Therapeutics,” 2nd edition, Totowa: Humana Press, 2006
  • Chadwick DJ, Good J, “Signaling Pathways in Acute Oxygen Sensing,” Chichester: John Wiley and Sons Ltd, 2006

Publications

Full list of publications at MSU Scholars

  • Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice. Yang M, Ramachandran A, Yan HM, Woolbright BL, Copple BL, Fickert P, Trauner M, Jaeschke H. Toxicol Lett. 2014 Jan 13;224(2):186-95. doi: 10.1016/j.toxlet.2013.10.030. Epub 2013 Nov 2.PMID: 24188933 [PubMed - in process]
  • Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Allen K, Jaeschke H, Copple BL. Am J Pathol. 2011 Jan;178(1):175-86. doi: 10.1016/j.ajpath.2010.11.026. Epub 2010 Dec 23. PMID: 21224055 [PubMed - indexed for MEDLINE] Free PMC Article
  • Effect of bile duct ligation on bile acid composition in mouse serum and liver. Zhang Y, Hong JY, Rockwell CE, Copple BL, Jaeschke H, Klaassen CD. Liver Int. 2012 Jan;32(1):58-69. doi: 10.1111/j.1478-3231.2011.02662.x. Epub 2011 Oct 17. PMID: 22098667 [PubMed - indexed for MEDLINE] Free PMC Article
  • Oxidative stress and the pathogenesis of cholestasis. Copple BL, Jaeschke H, Klaassen CD. Semin Liver Dis. 2010 May;30(2):195-204. doi: 10.1055/s-0030-1253228. Epub 2010 Apr 26. Review. PMID: 20422501 [PubMed - indexed for MEDLINE]