Genomic responses in mouse models poorly mimic human inflammatory diseases
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Genomic responses in mouse models poorly mimic human inflammatory diseases
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> vol. 110 no. 9
> Junhee Seok, 3507–3512
file:///E|/...ic%20responses%20in%20mouse%20models%20poorly%20mimic%20human%20inflammatory%20diseases.htm[8/28/2014 4:01:20 PM]
Genomic responses in mouse models poorly mimic human inflammatory diseases
Genomic responses in mouse models poorly
mimic human inflammatory diseases
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Junhee Seoka,1 ,
H. Shaw Warrenb ,1 ,
Alex G. Cuencac,1 ,
Michael N. Mindrinosa,
Henry V. Bakerc,
Weihong Xu a,
Daniel R. Richards d ,
Grace P. McDonald-Smith e,
Hong Gaoa,
Laura Hennessyf ,
Celeste C. Finnerty g ,
Cecilia M. López c,
Shari Honari f ,
Ernest E. Mooreh ,
Joseph P. Mineii,
Joseph Cuschieri j,
Paul E. Bankey k ,
Jeffrey L. Johnsonh ,
Jason Sperryl,
Avery B. Nathensm,
Timothy R. Billiar l,
Michael A. West n ,
Marc G. Jeschkeo ,
Matthew B. Klein j,
Richard L. Gamellip ,
Nicole S. Gibran j,
Bernard H. Brownstein q ,
Carol Miller-Grazianok ,
Steve E. Calvanor,
Philip H. Mason e,
J. Perren Cobbs,
Laurence G. Rahme t ,
Stephen F. Lowry r,2 ,
Ronald V. Maierj,
Lyle L. Moldawerc,
David N. Herndon g ,
Ronald W. Davis a,3 ,
Wenzhong Xiao a,t ,3 ,
Ronald G. Tompkinst ,3 ,
the Inflammation and Host Response to Injury, Large Scale Collaborative Research Program4
file:///E|/...ic%20responses%20in%20mouse%20models%20poorly%20mimic%20human%20inflammatory%20diseases.htm[8/28/2014 4:01:20 PM]
Genomic responses in mouse models poorly mimic human inflammatory diseases
1. aStanford Genome Technology Center, Stanford University, Palo Alto, CA 94305;
2. Departments of b Pediatrics and Medicine,
3. sAnesthesiology and Critical Care Medicine, and
4. t Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
5. cDepartment of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
6. d Ingenuity Inc., Redwood City, CA 94063;
7. eDepartment of Surgery, Massachusetts General Hospital, Boston, MA 02114;
8. f Department of Surgery, Harborview Medical Center, Seattle, WA 98195;
9. g Shriners Hospitals for Children and Department of Surgery, University of Texas Medical Branch,
Galveston, TX 77550-1220;
10. h Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
11. iDepartment of Surgery, Parkland Memorial Hospital, University of Texas, Southwestern Medical
Center, Dallas, TX 75390;
12. jDepartment of Surgery, Harborview Medical Center, University of Washington School of Medicine,
Seattle, WA 98195;
13. k Department of Surgery, University of Rochester School of Medicine, Rochester, NY 14642;
14. lDepartment of Surgery, University of Pittsburgh Medical Center Presbyterian University Hospital,
University of Pittsburgh, PA 15213;
15. mDepartment of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada M5B
1W8;
16. n Department of Surgery, San Francisco General Hospital, University of California, San Francisco, CA
94143;
17. o Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto,
Toronto, ON, Canada M4N 3M5;
18. p Department of Surgery, Stritch School of Medicine, Loyola University, Chicago, IL 60153;
19. q Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110; and
20. rDepartment of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson
Medical School, New Brunswick, NJ 08903
1. Contributed by Ronald W. Davis, January 7, 2013 (sent for review December 6, 2012)
Abstract
file:///E|/...ic%20responses%20in%20mouse%20models%20poorly%20mimic%20human%20inflammatory%20diseases.htm[8/28/2014 4:01:20 PM]
Genomic responses in mouse models poorly mimic human inflammatory diseases
A cornerstone of modern biomedical research is the use of mouse models to explore basic
pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to
carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models
mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory
stresses from different etiologies result in highly similar genomic responses in humans, the responses in
corresponding mouse models correlate poorly with the human conditions and also, one another. Among
genes changed significantly in humans, the murine orthologs are close to random in matching their human
counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model
systems, our study supports higher priority for translational medical research to focus on the more complex
human conditions rather than relying on mouse models to study human inflammatory diseases.
human disease
translational medicine
inflammation
immune response
injury
Footnotes
1 J.
Seok, H.S.W., and A.G.C. contributed equally to this work.
2 Deceased
June 4, 2011.
3 To
whom correspondence may be addressed. E-mail: dbowe{at}stanford.edu,
wxiao1{at}partners.org, or rtompkins{at}partners.org.
4A
complete list of the Inflammation and Host Response to Injury, Large Scale Collaborative
Research Program can be found in SI Appendix .
Author contributions: M.N.M., S.F.L., R.V.M., L.L.M., D.N.H., R.W.D., W. Xiao, R.G.T., and
I.H.R.I.,L.S.C.R.P. designed research; J. Seok, H.S.W., A.G.C., M.N.M., H.V.B., W. Xu, H.G., L.H.,
C.C.F., C.M.L., S.H., E.E.M., J.P.M., J.C., P.E.B., J.L.J., J. Sperry, A.B.N., T.R.B., M.A.W., M.G.J.,
M.B.K., R.L.G., N.S.G., B.H.B., C.M.-G., S.E.C., P.H.M., J.P.C., L.G.R., R.V.M., L.L.M., D.N.H., W. Xiao,
and R.G.T. performed research; J. Seok, W. Xu, D.R.R., H.G., R.W.D., and W. Xiao contributed new
reagents/analytic tools; J. Seok, A.G.C., H.V.B., W. Xu, D.R.R., H.G., C.C.F., C.M.L., and W. Xiao
analyzed data; and J. Seok, H.S.W., A.G.C., M.N.M., H.V.B., W. Xu, G.P.M.-S., L.L.M., W. Xiao, and
R.G.T. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1222878110/-/DCSupplemental.
Freely available online through the PNAS open access option.
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Genomic responses in mouse models poorly mimic human inflammatory diseases
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Related Letters
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and Peter Brouckaert
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doi:10.1073/pnas.1308333110
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Letter - Biological Sciences - Medical Sciences:
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Letter - Biological Sciences - Medical Sciences:
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Genomic responses in mouse models poorly mimic human inflammatory diseases
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Letter - Biological Sciences - Medical Sciences:
Ronald G. Tompkins,
H. Shaw Warren,
Michael N. Mindrinos,
Wenzhong Xiao,
and Ronald W. Davis
Reply to Osterburg et al.: To study human inflammatory diseases in humans PNAS 2013 110 (36) E3371;
published ahead of print July 11, 2013, doi:10.1073/pnas.1307452110
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Published online before print February 11, 2013, doi: 10.1073/pnas.1222878110
PNAS February 26, 2013 vol. 110 no. 9 3507-3512
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