Development of Small Molecule Proteasome Inhibitors

Jim Hayes,  Biology

Faculty Mentor: Dr. Sudhir Nayak

                Merck and AAAS have funded a three year grant at The College of New Jersey to develop small-molecule inhibitors of the proteasome. The proteasome is a large multi-protein complex which is found in the nucleus and cytoplasm of eukaryotes and whose main function is to break down damaged and unneeded proteins. Past research using RNA mediated interference (RNAi) in C. elegans has shown that certain genes, such as pbs-4 (Proteasome Beta Subunit), are vital in the normal function of the 26S proteasome.  Disruption of such genes results in a proteasome with altered function, therefore leading to improper breakdown of proteins and abnormal gene expression patterns. We are working to get similar divergent phenotypic expression by exposing C. elegans to various synthetic small-molecule proteasome inhibitors, rather than inactivating their proteasomes via RNAi.

              My project focused on identification of small molecules that result in the mis-expression of a germ-line protein GLD-1 (defective in Germ Line Development) tagged with GFP (green fluorescent protein). GLD-1 is an RNA binding protein that is integral in development of the germ-line in C. elegans.  The GFP allows us to visually observe where the tagged protein is being expressed throughout germline development.  The GLD-1 protein is normally degraded prior to oocyte development, releasing the bound RNA and allowing for the formation of oocytes.  However, when the proteasome is inactivated by means of RNAi, GLD-1 is not broken down at the proper location and is expressed beyond its normal range, resulting in the production abnormal oocytes. 

              As a first step towards our goals, a detailed analysis of phenotypes that result from loss of proteasome function is required.  Consequently, I have worked this summer to document the divergent expression patterns of GLD-1 when the proteasome is inactivated via RNAi.  Future work on this project will use my findings to gauge the efficacy the new, synthetic proteasome inhibitors developed by the Chemistry Department.

Personal Statement

              I have greatly enjoyed working in the Summer Undergraduate Research Program and I am convinced that this was one of the most beneficial things I could have done with my summer.  This program was an excellent opportunity to be immersed in the world of research, including doing actual lab work, conducting background research, troubleshooting problems, presenting current progress, and working collaboratively with other researchers. One of the best aspects of my summer experience was building and strengthening the relationships with the faculty in the Biology Department.  I felt as though we were all treated as research colleagues, having valid thoughts and opinions. My work was not trivial and irrelevant, but rather it had worth and merit and was respected by the department. I can honestly say that my participation in SURP has been one of the most valuable experiences I have had while at The College of New Jersey.   It has shown me that I seriously do enjoy research, but more importantly, it has strengthened my resolve to continue my studies for a post-graduate degree.