This proposal integrates interests and training in clinical neurobiology and basic molecular biology; the long term objective is an understanding of neural trophism and plasticity, and their relevance to neuro-oncology. Previous work demonstrated that autoantibodies present in patients with neurologic disease and occult malignancy bind antigens (termed 'onconeural') that are coordinately expressed in neurons and tumor cells; these autoantibodies can be used to clone onconeural genes. It is hypothesized that there are specific signal transduction pathways shared by tumor cells and neurons. Two candidate pathways, not necessarily exclusive, are suggested: proto-oncogene and onconeural pathways. An experimental protocol is suggested to identify onconeural autoantibodies from patients with neurologic disease, and use them to clone genes from lambda gt11 expression vectors. DNA sequence data will give preliminary information about the function of these genes. To test the relationship between neural and growth control pathways, full length cDNA's will be transfected into various cell lines and assayed for transforming activity. Conversely, proto-oncogenes and onconeural genes will be tranfected into neural cells and assayed for a role in neural trophism and plasticity. Clinical information regarding the patients neurologic disease and malignancy will be correlated with the study of their autoantibodies. These experiments will be related both to basic mechanisms of neurophysiology and growth control, and a number of clinical problems. These include the regulation of neuron-specific genes, the regulation of growth control pathways in tumors, the identification of tumor specific antigens of potential diagnostic and therapeutic importance, the identification of factors and pathways that may be involved in neural trophism and neurodegenerative disease, and mechanisms of autoimmune disease.
