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F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
The Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute is a multidisciplinary basic, translational and clinical research program devoted to mucosal inflammation. Under the direction of Stephan R. Targan, MD, the Institute is the overarching administrative structure of three distinct yet highly interactive sub-units: IBD Clinical Care and Trials, Translational Research and Basic Science Laboratory Research.
Investigators at the Institute apply the combinatorial genomics approach to mucosal inflammatory diseases, which involves associating genes with several serological markers we have identified. Combining these markers with a genome-wide association study (GWAS), we found several gene regions with great potential to be involved in these disorders. This information is used to identify targets for therapeutic development and to generate mouse models for further in vivo animal investigation. Other work focuses on genetic and immunologic pathway associations with severity of disease.
We now know that there is a subset of patients with aggressive/progressive disease who have multiple- and high-level responses to bacterial pathogens and that there is also a subset of patients with mild disease with no or low reactivity to these pathogens. By studying samples from these patients at opposite ends of the disease spectrum, we are beginning to narrow in on the genes responsible for the body’s reactions to the pathogens. Based on the results from the genome-wide scan, focused by specific immunologic profiles, genetic variants have been identified that are associated with Crohn’s disease. The immune response and the abnormal pathways that are associated with it are keys to understanding how inflammation occurs in inflammatory bowel disease. In this case, research in humans led to a new understanding of one of our animal models, and the information from the animal models advanced our research in humans: bench to bedside and back to bench.
While one patient may have IBD as a result of one gene variant and one pathway abnormality, another may have IBD as a result of a different or multiple gene variants and different or multiple pathway abnormalities. It is well established that proteins known as cytokines play a role in the inflammatory process. One example is TL1A, a newly discovered protein that has been shown to play a key role in IBD. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute has been a critical leader in the effort to understand how TLIA works in IBD. We have an advantageous position to maximize what we can learn from proteins like TL1A and their associated pathways because we know how they are controlled and we have access to an antibody that can regulate its effects. TL1A is central to the way in which several immune cells respond to initiate and perpetuate the immune response type associated with Crohn’s disease. With such a major role in the inflammatory process, it is probable that modulating the effects of TL1A will be a strong target for the development of therapeutics to treat a subpopulation of Crohn’s disease patients who have been defined by the basic science experiments described above.
In Vivo Target Development
Very often, the process of developing animal models to study the effect of certain variants on pathways leads to additional findings that initiate further investigation using human materials. Once again, returning to the TL1A example described above, we performed parallel studies in animal models to more fully understand the relationship of TL1A to intestinal inflammation. Mouse studies are crucial because their immunology can be manipulated and altered to isolate different effects of different proteins, as well as the effect on specific cell types in specific parts of the body.
Once again, returning to the TL1A example described above, we performed parallel studies in animal models to more fully understand the relationship of TL1A to intestinal inflammation. Mouse studies are crucial because their immunology can be manipulated and altered to isolate different effects of different proteins, as well as the effect on specific cell types in specific parts of the body. The possibilities are practically endless, yet the information yielded is very specific. Some disease mechanisms are clearly relevant in both mouse and human disease, determining which animal models and what mechanisms may be relevant to human disease has been somewhat difficult. Inflammation in these animal models is highly variable even to the degree seen among patients with inflammatory bowel disease. Using our knowledge of TL1A, we assessed whether it will be a good therapeutic target and the early data are very encouraging. Because of the success of this treatment in animals, testing is now beginning in humans.