Quebec - Dr. Jean-Luc Senecal, University of Montreal

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Original Research Projects of the Scleroderma Research Group

The primary objective of the Scleroderma Research Group (SRG) is to identify new treatments to block the devastating biological events leading to scleroderma. In order to achieve this objective, we need to better understand how these events take place. The following projects will allow the SRG to attain its primary objective. Note that these are original SRG projects, i.e. to our knowledge, they are not being pursued by other research groups.

Identification and characterization of a new molecule found on the surface of fibroblasts : pathogenic and diagnostic implications. SRG researchers have recently discovered that peculiar antibodies are present in the blood of scleroderma patients. These antibodies react with an unknown molecule at the surface of cells called fibroblasts. The antibodies are present only in the blood of scleroderma patients and not in normal individuals or in people with other diseases. This is a major step in scleroderma research. Because these antibodies are directed against their own cells of scleroderma patients, they are called autoantibodies, “auto” meaning “self”.

This discovery is extremely intriguing, because the skin thickening and involvement of internal organs that characterize scleroderma are caused in part by dysfunction of fibroblasts. These fibroblasts produce massive amounts of collagen, causing a fibrosis which disrupts body functions. However the reason remains unknown why fibroblasts behave so abnormally in scleroderma. Therefore this exciting discovery begs the question: could these autoantibodies be the triggering factor of the disordered fibroblast behavior? Specifically, SRG researchers wish to answer the following questions. What is the identity of this molecule at the surface of fibroblasts? Is it a protein ? Is it a cell surface receptor? Why is this autoantibody unique to scleroderma patients? Could screening for these antifibroblast autoantibodies be useful in diagnosing and treating scleroderma? Or is the presence of these autoantibodies linked to a particular patient subset of the disease, and if so, then why?

The fibrogenic role of antifibroblast autoantibodies. This project has a tight link with the previous one. Its goal is to analyze the consequences of the binding between the autoantibodies and the molecule at the surface of the fibroblasts. In particular, the project will determine whether this binding triggers and perpetuates the excessive production of collagen by fibroblasts that is so characteristic of scleroderma. If the answer is positive, the project will then ask : is it possible to block the binding of antifibroblast autoantibodies to this rnolecule in order to prevent the devastating effects of scleroderma?

Tissue engineering of scleroderma skin to decipher the mechanisms causing fibrosis in scleroderma. This cutting-edge project consists in obtaining skin biopsy samples from scleroderma patients. These samples of living skin are grown in culture in the laboratory and their constitutive cell populations are then separated. The next step will be to reunite selectively these cells to observe how they grow together, and what components are required to rebuild a scleroderma skin. This is a highly novel and original approach to study the crosstalk (communication) between cells.

The role of autoantibodies in vascular lesions. The SRG proposes research in another new area, namely the study of vascular damage in scleroderma using human cells, with specific emphasis on autoantibodies as contributors to the severe organ damage that characterizes this disease. This project will specifically address how autoantibodies characteristic of scleroderma, such as anticentromere and anti-topoisomerase I autoantibodies, are pathogenic (i.e. cause disease lesions). The originality of this project is the use of living human vascular cells similar to those that are targeted in scleroderma. For example, if the SRG demonstrates that exposing these cells to scleroderma autoantibodies does reproduce scleroderma vascular lesions, this would be a breakthrough, as such a role has never been shown. The SRG would then focus on using this model to block the detrimental effects of the autoantibodies on patients, or perhaps to prevent vascular damage in people at-risk.

The mechanisms of apoptosis in scleroderma. Programmed cell death (apoptosis) plays a crucial role in many normal physiological functions. Disordered apoptosis has been found to contribute to diseases such as cancer, AIDS and autoimmune diseases, such as systemic lupus erythematosus. Studies on animal models of scleroderma suggest that underlying apoptotic abnormalities may be present in human scleroderma. However, the apoptotic mechanisms have not been studied in-depth in humans with scleroderma. By identifying disorders of apoptosis in scleroderma, SRG researchers will understand better the pathologic physiology of scleroderma in order to devise better targeted therapies which will be both more effective and less toxic.

Genetics of scleroderma. In the last few years, genetic research has extraordinarily expanded worldwide. The importance of genetic aspects of disease has been demonstrated in various areas of medicine. The vitality of genetic research in Québec was shown in 2001 by the founding of "Génome Québec", in-keeping with the highest international standards. Genetic abnormalities have been identified in a mouse model of Scleroderma. In humans, genetic abnormalities have been reported in Choctaw Indians of the United States, who are frequently afflicted with scleroderma. In the Province of Québec, there are a significant number of families in which two or more members are afflicted with the disease, suggesting that genetic factors are present. Until now, genetic anomalies have not been studied in French Canadian scleroderma patients. The results of this study will help to better understand the genetic factors which lead to the development of scleroderma.

Development of new treatments for scleroderma. This is the ultimate objective of all the preceding fundamental research projects. By deciphering the mechanisms leading to fibrosis and vascular damage in scleroderma, the SRG aims at developing new therapeutic molecules that will block the biological events leading to the mummification process of scleroderma.