Grant: Project Grant

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately one in every 1000 Canadians, and can result in life-long suffering and premature death. Individuals with SLE develop an immune response against their own cells, but it is not known how or why this abnormal immune response arises. Treatment of SLE often involves broad suppression of the immune response, with consequences for the patient's resistance to infection. A better understanding of how SLE arises will lead to more selective drugs that target the specific biological processes that cause SLE. The aim of the proposed research is to investigate how SLE originates. Using an animal model of SLE developed by us, we identified an important protein called "RIPK3". RIPK3 regulates cell death and inflammation, and is essential for the development of SLE in our animal model. In this study, we will determine whether RIPK3-dependent effects on cell death or inflammation, or both, are responsible for murine SLE. Moreover, we will ask whether RIPK3-dependent cell death is increased in cells from SLE patients, and, if so, how the patient's immune system responds to dying cells. For our murine model, we will use mice that are deficient in either cell death or inflammation processes regulated by RIPK3 to identify which of these processes is required for initiating SLE. We will then use drugs (pharmacologic agents) to specifically block these RIPK3-dependent processes. Our research in animal models will provide proof that targeting RIPK3-dependent mechanisms may lead to the prevention or improvement of SLE. Our findings with human cells will indicate whether RIPK3-dependent cell death is important in human SLE. In summary, our proposed research has the potential to generate a novel innovation that can impact both knowledge about SLE and patient care. An improved understanding of SLE will ultimately result in better treatment and prevention of this chronic and debilitating disease.