Myasthenia gravis (MG) is an autoimmune disease, caused by antibodies directed at the skeletal muscle nicotinic acetylcholine receptor. MG continues to be a significant cause of impaired vision despite advances in treatment and understanding of its pathophysiology. Weakness of extraocular muscle (EOM) occurs in about 90 percent of myasthenics and 15 percent of all myasthenics will only manifest ocular signs. Why EOM is affected more prominently than extremity muscle is not understood. We hypothesize that EOM is preferentially affected by the autoimmune process because it contains unique epitopes which are differentially targeted for auto-immune mediated damage by MG. Unlike extremity skeletal muscle, mammalian EOM contains multiply-innervated fibers. Dr. Kenichiro Oda has identified antibodies from ocular myasthenics' sera whiCh bind exclusively to the endplate region of the multiply-innervated fibers. In Phase 1 of the training program, we will use Dr. Oda's antibodies to screen a human EOM cDNA expression library to identify fusion proteins which bind these antibodies. DNA sequences of the fusion proteins will be analyzed for similarities to known acetylcholine receptor subunits and endplate proteins. In Phase 2 of the research plan, the pathogenic nature of these proteins will be assessed by development of an enzyme-linked immunosorbent assay for ocular and generalized MG and animal model of ocular MG. The research program offers an ideal training program for the Principal Investigator, Dr. Kaminski. Phase 1 serves to teach fundamental molecular biological techniques, while Phase 2 leads to application of these methods to an important clinical problem. The long term goals of this project are to develop new treatment modalities for MG and improved understanding of the EOM function.
