Grant Award 011

Abbreviated Title of Research Proposal: “Probing the role of GNE in HIBM”

Project Summary: Sialic acid is an unusual form of sugar that decorates the surfaces of human cells and plays many important biological roles in healthy cells; conversely abnormalities to the production of this sugar are associated with several important human diseases including cancer. For example, hereditary inclusion body myopathy (HIBM) is a disease associated with mutations to UDP-GlcNAc 2-epimerase / ManNAc 6-kinase (GNE). This enzyme plays a key role in controlling metabolic flux into the sialic acid biosynthetic pathway and can thereby regulate cellular production of this important sugar suggesting that HIBM may be caused by changes in the pattern of sialic acid found on the cell surface. Preliminary evidence, however, indicates that this most obvious explanation for on the underlying cause of HIBM is not correct (or at minimum, is incomplete). Our laboratory has developed methods to manipulate sialic acid metabolism in living cells in ways that mimic the suspected effects of the mutant form of GNE in HIBM patients. The first goal of our experiments using these methods is to conclusively address the question “Is HIBM a disease of sialic acid metabolism?” If the answer is “yes”, we are developing treatment strategies to increase sialic acid production in cells by supplementing them with metabolic intermediates or replacing the defective form of GNE by gene therapy methods. If the answer is “no”, we are undertaking DNA microarray and proteomic experiments to uncover the real mechanism by which mutant forms of GNE harm muscle cells.