Center for Inflammation and Regeneration Modeling (CIRM)

Advancing Medicine Today:

CIRM-Puzzle The McGowan Institute for Regenerative Medicine was established by the University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center (UPMC) to explore the vast potential of tissue engineering and other techniques for repairing damaged or diseased tissues and organs. The McGowan Institute serves as a single base of operations for the University’s leading scientists and clinical faculty members who are working to develop tissue engineering, cellular therapies, biosurgery, and artificial and biohybrid organs.

To investigate the complex process of inflammation and its relationship to regenerative medicine, the McGowan Institute established the Center for Inflammation and Regeneration Modeling (CIRM).

Why regenerative medicine?

The human body has an inherent ability to repair many of its own organs and tissues following damage from either disease or trauma. One goal of medicine has been to facilitate this intrinsic self-renewing ability by relieving damaged tissues of their functional burden and providing what was empirically perceived to be the ideal environment for tissue healing.

During the last century, newer concepts emerged, including replacement of diseased tissues with synthetic materials — such as heart valves and artificial joints — and, more recently, transplanted organs and engineered tissues. In many cases, the patient has suffered such significant and irreparable tissue damage that the only option to restore function is an implant or organ transplant.

We believe that a large number of patients with organ failure would be better served by modalities of treatment that embrace the historic principle of medicine: optimizing the regenerative potential intrinsic to many organ systems.

We study regenerative medicine to understand how we can facilitate the body’s ability to heal itself.

Why study inflammation?

To achieve this goal, we must understand and acknowledge the pivotal role of inflammation — first, in the initial damage process and then, in the various aspects of the healing response and tissue remodeling following injury.

Inflammation can be described as a process initiated by various insults to the organism and resulting in organ damage or dysfunction. Therapeutic approaches involving temporary organ support, which are designed to allow the injured organ to regain function, often themselves cause additional inflammation because of the technique or device used or the invasive procedure necessary to implement the therapy.

Inflammation involves both innate and adaptive immune elements, the endothelium, the complement and coagulation cascades, and the modulatory role of therapeutic compounds, devices, and strategies. Both acute and chronic inflammation are highly intricate processes that are induced by various insults to a tissue or organ, modulated by numerous cells and cell products, and affect different tissues in diverse ways.

Despite enormous progress in studying the human immune system, a holistic understanding of the immune/inflammatory response is not yet in grasp. The lack of a comprehensive framework to investigate and understand this complex phenomenon hinders the design of optimal preclinical and clinical studies aimed at developing effective therapies in regenerative medicine.

We study inflammation because this highly complex process is central to regeneration.

CIRM2 The Center for Inflammation and Regeneration Modeling employs a systems approach — a means for understanding complex biological processes as a whole

The Center for Inflammation and Regeneration Modeling was established to address the need for a unified, systems framework to tackle the complexity of the inflammatory response — in the setting of regenerative medicine and beyond.

CIRM is headed by Yoram Vodovotz, PhD, director (University of Pittsburgh School of Medicine, Department of Surgery) and Gilles Clermont, MD , MSc, , medical director (University of Pittsburgh School of Medicine, Department of Critical Care Medicine).

Integral parts of CIRM include its three cores: Modeling, Educational, and Data Analysis. This framework is designed to train interdisciplinary scientists in the emerging discipline of inflammation modeling, to characterize several scenarios of relevance to regenerative medicine, and to identify new therapeutic approaches.

A New Paradigm

By employing high-throughput technologies, “systems biology” has emerged as a new paradigm that allows the study of large portions of physiological networks simultaneously, using genomic, proteomic, and metabolomic biomarker profiling to understand the behavior of the system as a whole. These approaches must be coupled with mathematical modeling of complex systems in order to tame the seemingly unpredictable behavior of such biological phenomena and to account for the plethora of known and unknown interactions among biologic pathways. Only then can we control and possibly harness the inflammatory process for the purpose of regenerative medicine.

Initial efforts in the field of inflammation modeling

The CIRM team includes clinicians, biologists, mathematicians, statisticians, and computer scientists engaged in a multidisciplinary effort to solve the puzzle of acute inflammation and organ failure in the setting of trauma and sepsis.

This team is carrying out an iterative program of model generation, verification, and calibration in both animals and humans, and subsequent hypothesis generation and testing in the setting of acute inflammation. Investigators have also incorporated mechanistic models of wound healing to create preliminary mathematical models of inflammation, organ damage and dysfunction, and wound healing.

Goals of the Center for Inflammation and Regeneration Modeling

CIRM has set three primary goals:

To bring to bear on the problem of acute and chronic inflammation interdisciplinary input and enthusiasm of clinicians, bench scientists, and modelers, from both research institutions and companies.
To facilitate the design of regenerative medicine approaches by elucidating the underlying inflammatory processes and the inflammatory impact of various therapies.
To understand and harness the intrinsic regenerative power of the human body by modeling not only specific organs but also the inflammatory communication network that binds them together.

These goals are accomplished by:

Recruiting modelers from the University of Pittsburgh, Carnegie Mellon University, and industry to address practical clinical problems.
Creating a vast repository of relevant patient-centered and research data, including high-density physiologic measurements, gene/protein data, imaging data, clinical process/therapeutic data, and administrative and demographic data, as well as tools to mine these data in a way that is immediately relevant to modelers.
Creating an interdisciplinary educational curriculum for a new generation of scientists studying the biology of inflammation.
Creating opportunities for partnerships with industry commercialization of novel therapeutics.

Share the commitment

The Center for Inflammation and Regeneration Modeling is a new initiative, but its base institutions, affiliations, facilities, and talent pool are well established and substantial. We have a long-term interest in the mission of CIRM, and we invite other professionals who share our commitment to join us in this dynamic, interdisciplinary enterprise.

CIRM Faculty

Center for Inflammation and Regeneration Modeling (CIRM) faculty members:

Shared Models and Simulations

Northwestern (Innate Immune Response) (Gut Epithelial Barrier)
SPARK: An Agent-based Model Framework developed by CIRM

Models

Kumar, R.; Clermont, G.; Vodovotz, Y.; Chow, C. C. The dynamics of acute inflammation. J.Theoretical Biol. 2004. 230:145-155
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Clermont, G.; Bartels, J.; Kumar, R.; Constantine, G.; Vodovotz, Y.; Chow, C. In silico design of clinical trials: a method coming of age. Crit Care Med. 2004. 32:2061-2070
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Chow, C. C.; Clermont, G.; Kumar, R.; Lagoa, C.; Tawadrous, Z.; Gallo, D.; Betten, B.; Bartels, J.; Constantine, G.; Fink, M. P.; Billiar, T. R.; Vodovotz, Y. The acute inflammatory response in diverse shock states. Shock 2005. 24:74-84
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Reynolds, A.; Rubin, J.; Clermont, G.; Day, J.; Vodovotz, Y.; Ermentrout, G. B.. A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation. J.Theor.Biol. 2006. 242:220-236
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Day, J.; Rubin, J.; Vodovotz, Y.; Chow, C. C.; Reynolds, A.; Clermont, G.. A reduced mathematical model of the acute inflammatory response: II. Capturing scenarios of repeated endotoxin administration. J.Theor.Biol. 2006. 242:237-256
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Prince, J.M.; Levy,R.M.; Bartels, J.; Baratt, A.; Kane, J.M. III; Lagoa, C.; Rubin, J.; Day, J.; Wei, J.; Fink, M.P.; Goyert, S.; Clermont, G.; Billiar, T.R.; Vodovotz, Y. In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice. Mol. Med., 2006. 12:88-96
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Lagoa, C.E.; Bartels, J.; Baratt, A.; Tseng, G.; Clermont, G.; Fink, M.P.; Billiar, T.R.; Vodovotz, Y. The role of initial trauma in the host’s response to injury and hemorrhage: Insights from a comparison of mathematical simulations and hepatic transcriptomic analysis. Shock, 2006. 26:592-600
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Mi, Q.; Rivière, B.; Clermont, G.; Steed, D.L. ; Vodovotz, Y. Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-?1. Wound Repair Reg. 2007. 15:671-682
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Mi, Q.; Rivière, B.; Cetin, S.; Swigon, D. ; Vodovotz, Y. ; Hackam, D. One-dimensional elastic continuum model of epithelial wound healing. Biophys. J. 2007. 93:3745-3752
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Kumar, R.; Chow, C.C.; Bartels, J.; Clermont, G.; Vodovotz, Y. A mathematical simulation of the inflammatory response to anthrax infection. Shock. 2008. 29:104-111
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Li, N.Y.K.; Verdolini, K.; Clermont, G.; Mi, Q.; Hebda, P.A.; Vodovotz, Y. A patient-specific in silico model of inflammation and healing tested in acute vocal fold injury. PLoS ONE. 2008. 3:e2789.
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Daun, S.; Rubin, J.; Vodovotz, Y.; Roy, A.; Parker, R.; Clermont, G. An ensemble of models of the acute inflammatory response to bacterial lipopolysaccharide in rats: Results from parameter reduction. J. Theoretical Biol. 2008. 253:843-853
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Rivière, B.; Epshteyn, Y.; Swigon, D.; Vodovotz, Y. A simple mathematical model of signaling resulting from the binding of lipopolysaccharide with Toll-like receptor 4 demonstrates inherent preconditioning behavior. Math. Biosci. 2009. 217:19-26
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Torres, A.; Bentley, T.; Bartels, J.; Namas, R.; Zamora, R.; Puyana, J.C.; Vodovotz, Y. Mathematical modeling of post-hemorrhage inflammation in mice: Studies using a novel, computer-controlled, closed-loop hemorrhage apparatus. Shock. 2009. 32:172-178
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Li, N.Y.K.; Vodovotz, Y.; Hebda, P. Verdolini, K. Biosimulation of inflammation and healing in surgically injured vocal folds. Ann. Otology Rhinol. Laryngol. 2010. 119:412-423
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Brown, B.; Price, I.; Toapanta, F.R.; DeAlmeida, D.R.; Wiley, C.A.; Ross, T.M.; Oury, T.D.; Vodovotz, Y. An Agent-based model of inflammation and fibrosis following particulate exposure in the lung. Math. Biosci. 2011. 231:186-196
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Mi, Q.; Constantine, G.; Ziraldo, C.; Solovyev, A.; Torres, A.; Namas, R.; Bentley, T.; Billiar, T.R.; Zamora, R.; Puyana, J.C.; Vodovotz, Y. A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks. PLoS ONE. 2011.6:19424
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Li, N.Y.K.; Vodovotz, Y.; Kim, K.H.; Mi, Q.; Hebda, P.A.; Verdolini Abbott, K. Biosimulation of acute phonotrauma: An extended model. Laryngoscope 2011. 121:2418-2428
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Nieman, G.; Brown, D.; Sarkar, J.; Kubiak, B.; Ziraldo, C.; Dutta-Moscato, J.; Vieau, C.; Barclay, D.; Gatto, L.; Maier, K.; Constantine, G.; Billiar, T.R.; Zamora, R.; Mi, Q.; Chang, S.; Vodovotz, Y. A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine: Insights from combined data-driven and mechanistic modeling. Crit. Care Med. 2012. Apr;40(4):1052-1063
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