- Dr. Jiangping Wu, Principal Investigator
- Notre-Dame Hospital, University of Montreal, Montreal, Canada
- To Improve Outcomes of Organ Transplantation by Inhibiting Function of a "Garbage Collector" Proteosome
The proteosome is a protein complex whose job is to degrade most of the proteins in a cell. It was considered as a "garbage collector" of cells, and its role in cells was thought humble and insignificant. Our recent work shows that function of the proteosome is tightly regulated and it plays critical roles in controlling cell growth and death. Notably, we have found that if activity of the proteosome is inhibited, cells that are vigorously growing will be easily killed, while cells that are not growing will be spared. This is a very interesting feature, and we will take advantage of it to improve outcomes of organ transplantation.
Organ transplantation is an effective way to treat various end-stage diseases of various organs. After organ transplantation, a graft will be rejected by a recipient because the immune system of the recipient will recognize the graft as a foreign entity. T lymphocytes of the immune system play a major role in the graft rejection. Some T cells are specific to foreign molecules (called alloantigen) of the graft and are stimulated by these molecules. These cells will start to grow and to proliferate and finally cause damage to the graft, while other irrelevant T cells that might be protective against microbes remain in a resting status. If we kill the growing T cells, then we can create a hole in the immune system such that it cannot reject the graft but its protective functions against other microbes remain intact. Our final objective is to use proteosome inhibitors to inhibit T cell proliferation and to kill alloantigen-specific T cells after organ transplantation with a view to controlling graft rejection and creating long-term graft tolerance. In this project, we will conduct a proof of concept study on the toxicity, pharmacokinetics and efficacy of a prototype proteosome inhibitor lactacystin in living mice. If these parameters are acceptable, we will then be able to proceed to achieve our final objective.