Gastroenterology

CELLULAR AND MOLECULAR MECHANISMS OF ORGAN INJURY

Brief Description

As our basic understanding of organ injury expands, so do treatment options for important human diseases. The combined molecular and cellular approaches that this group offers, derived from a variety of disciplines, exhibits a single focus, namely determining the molecular and cellular basis of organ injury. This established group is the academic thrust of the Multi-Organ Transplant Program at the University of Toronto. The objective of the group is to utilize candidate and novel models of cellular activation, each having a unique relevance to diseases of organs, to develop important new insight into complex biological processes. Organ dysfunction is recognized as the most clinical serious manifestation arising from insult at the cellular and molecular level.  A remarkable feature of organ injury is the homogenous nature of the pathophysiological changes that occur in individual organs following response to a broad range of seemingly dissimilar exogenous stimuli.  This group, while originating conceptually in studies in a variety of cell types, seeks to contribute to understanding organ dysfunction on a mechanistic basis. The group brings together expertise in the biology and pathobiology of cytokines, viruses, cell-cell interactions, immune-mediated injury, excitation-contraction coupling and gene transcription networks. The expertise is combined in cellular/molecular dissection of organ injury, furthered by the study of novel mechanisms in the group setting. Thus, the aims of the group are:

• to promote scientific excellence and advance the state of knowledge in the area of scientific inquiry by bringing together a group of researchers with different areas of expertise;
• to promote research that allows scientific advances to move from the bench to the bedside, with the aim of impacting both on care for individual patients and health care in general;
• to foster an environment for the training of students and post-doctoral fellows for the development of future scientists.

Principal Investigators

Recent Original Research Publications

Zhang Z-X, Yang L, Young KJ, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression Nat Med 6:782, 2000.

Fan J, Kapus A, Marsden PA, Li YH, Oreopoulos G, Marshall JC, Frantz S, Kelly RA, Medzhitov R, Rotstein OD.  Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and  lipopolysaccharide. J Immunol 168:5252-9, 2002.

Chan CW, Chan MW, Liu M, Fung L, Cole EH, Leibowitz JL, Marsden PA, Clark DA, Levy GA.   Kinetic analysis of a unique direct prothrombinase, fgl2, and identification of a serine residue critical for the prothrombinase activity. J Immunol 168:5170-7, 2002.

Barlic J, Andrews JD, Kelvin AA, Bosinger SE, DeVries ME, Xu L, Dobransky T, Feldman RD, Ferguson SS, Kelvin DJ. Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol 1:227-33, 2000.

Kruger JM, Fukushima T, Cherepanov V, Borregaard N, Loeve C, Shek C, Sharma K, Tanswell AK, Chow CW, Downey GP. Protein-tyrosine phosphatase MEG2 is expressed by human neutrophils. Localization to the phagosome and activation by polyphosphoinositides. J Biol Chem 277:2620-8, 2002.

Future Directions

The program is now undertaking studies in three main areas:

• understanding mechanisms of inflammatory processes, including viral induced tissue injury; allo- and xenograft rejection and endothelial cell activation.
• studies of  mechanism and barriers to tolerance induction including the use of  gene microarrays and proteomics utilizing tissues from small animal (rodent),  non-human primates, and humans.
• studies of  gene and cell therapy to modify the environment of transplanted tissues and organs in  an attempt to produce a state of tolerance both for successful allo and xeno transplantation; but also for treatment of autoimmune diseases.