Grant Award 013

Principal Investigator: Masashi Kitazawa, PhD
Abbreviated Title of Research Proposal: Impact of Ab on GNE transgenic mice

Project Summary: Hereditary inclusion body myopathies (h-IBM) are devastating and progressive muscle weakening disorders that eventually cause paralysis. h-IBM is a human genetic disease and inherited among certain families. Unfortunately, no effective treatment or cure has been developed for these disorders, and disease may begin as early as 20 years of age. Among h-IBM, one particular type called IBM2 shows a high prevalence among Iranian-Jewish families. Studies discovered that affected individuals and their family members have a genetic mutation in the GNE gene. Although the gene of interest for the disease was identified, it is difficult to conduct further research to find the mechanism of the disease progression and treatments using human. Because of the importance of developing non-human subjects that mimic the key pathology of IBM2, we propose to develop a mouse model for IBM2. Two human genes, GNE and APP, another important gene that may play a role in the h-IBM as well as the sporadic form of IBM, are being studied. We will make mice processing these two human genes and selectively produce these proteins in skeletal muscle. Motor performance and muscle pathology of these mice will be examined to determine whether or not these mice show similar pathology with IBM2. These results will provide the evidence not only that these genes, GNE and APP, play critical roles in the development of IBM2-like pathology, but also these mice may be useful tools to study potential therapeutic approaches for IBM2. After the characterization of this mouse model, we will conduct a series of studies to evaluate the effect of immunotherapy. These studies will provide further insights into understanding of IBM2.