Genomic responses in mouse models poorly mimic human inflammatory diseases

Junhee Seok1, H. Shaw Warren2, Alex G. Cuenca3, Michael A. West1, Henry V. Baker3, Weihong Xu1, Daniel R. Richards4, Grace P. McDonald-Smith5, Hong Gao1, Laura Hennessy6, Celeste C. Finnerty7, Cecilia M. López3, Shari Honari6, Ernest E. Moore8, Joseph P. Minei9, Joseph Cuschieri10, Paul E. Bankey11, Jeffrey L. Johnson8, Jason L. Sperry12, Avery B. Nathens13, Timothy R. Billiar12, Marc G. Jeschke14, Matthew B. Klein10, Richard L. Gamelli15, Nicole S. Gibran10, Bernard H. Brownstein16, Carol Miller‐Graziano11, Steve E. Calvano17, Philip H. Mason5, J. Perren Cobb18, Laurence G. Rahme19, Stephen F. Lowry17, Ronald V. Maier10, Lyle L. Moldawer3, David N. Herndon7, Ronald W. Davis1, Wenzhong Xiao20,19, Ronald G. Tompkins19, Amer Abouhamze, Kristin Burnum-Johnson, Asit K. De, Brian G. Harbrecht, Ivor S. Douglas, Amit Kaushal, Grant E. O’Keefe, Kenneth T. Kotz, Weijun Qian, David Schoenfeld, Michael B. Shapiro, Geoffrey M. Silver, Richard Smith, John D. Storey, Robert Tibshirani, Mehmet Toner, Julie Wilhelmy, Bram Wispelwey, Wing H. Wong
1Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94305;
2Departments of bPediatrics and Medicine,
3Department of Surgery, University of Florida College of Medicine, Gainesville FL 32610
4Ingenuity Inc., Redwood City, CA 94063;
5‡Department of Surgery, Massachusetts General Hospital, Boston, MA 02114;
6Department of Surgery, Harborview Medical Center, Seattle, WA 98195;
7Shriners Hospitals for Children and Department of Surgery, University of Texas Medical Branch, Galveston, TX 77550-1220;
8Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
9Department of Surgery, Parkland Memorial Hospital, University of Texas, Southwestern Medical Center, Dallas, TX 75390;
10Department of Surgery, Harborview Medical Center, University of Washington School of Medicine, Seattle, WA 98195;
11Department of Surgery, University of Rochester School of Medicine, Rochester, NY 14642;
12Department of Surgery, University of Pittsburgh Medical Center Presbyterian University Hospital, University of Pittsburgh, PA 15213;
13Department of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada M5B 1W8;
14Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada M4N 3M5;
15Department of Surgery, Stritch School of Medicine, Loyola University, Chicago, IL 60153;
16Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110; and
17Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903
18Anesthesiology and Critical Care Medicine, and
19Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
20Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94305;; Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;

Tóm tắt

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., R 2 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.

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Tài liệu tham khảo

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