Project Summary This resubmission proposal aims to elucidate the role of a histone deacetylase, HDAC11, in diseases such as multiple sclerosis (MS), and to establish HDAC11 inhibition as a potentially effective new treatment strategy for diseases including MS. MS is a chronic, immune-mediated demyelinating disease of the central nervous system. Like many autoimmune disorders, it presently has no known cure, and current drugs available for managing this disease are only effective early on and are accompanied by many adverse effects. The disease mechanism of MS remains unclear, and no effective targeted therapy is available for chronic progressive MS. Our preliminary studies show that deletion of HDAC11 ameliorates clinical symptoms in a mouse model of MS. In parallel, we discovered a novel HDAC11 enzymatic activity that is >10,000-fold more efficient than its deacetylase activity. This novel activity allows us to begin to uncover physiologic substrates of HDAC11, which in turn will help to uncover the biological mechanisms of HDAC11’s actions. One of the goals of this research is to investigate how this newly discovered enzymatic activity underlies the immune-regulatory function of HDAC11 in MS. Knowledge gained from these studies will help to further understand the disease mechanism of MS and to develop better therapeutics. Because the discovery of a novel HDAC11 activity has enabled us to develop, for the first time, HDAC11-specific inhibitors, the chief objective is to further improve these inhibitors and test whether they can be used to treat diseases such as MS in our established mouse models. Our multidisciplinary team has expertise in all aspects needed to make this project successful. Overall, the proposed studies in this application will not only yield a better understanding of HDAC11’s function in health and diseases, but may also result in a first prototype targeted therapy for the treatment of chronic progressive MS, and possibly other diseases as well.