We propose using transgenic mice to study the effects of virally encoded proteins on the nervous, immune and muscular systems. Proteins are targeted to specific tissues in mice by use of engineered expression vectors. constructed to give high levels of tissue specific protein products. Two models will be utilized. The first continues studies on an established transgenic line (1-3). These mice express the HTLV-I tat protein and develop peripheral perineurial tumors, salivary gland tumors, and skeletal muscle atrophy. The perineurial tumors are of interest, because of their resemblance to the human disease, von Recklinghausen's neurofibromatosis (VRN). Tissues from these mice will be used to create cDNA libraries which will be screened against normal and transgenic tissues to identify messages induced by the tat gene. Newly identified genes will then be used to screen tissue from humans with VRN for expression of these gene products. Parallel studies will investigate the role of HTLV-I in the etiology of VRN. The second transgenic model will be generated using the Thyl.2 gene as an expression vector to target other viral proteins to the CNS and thymocytes/lymphocytes of mice. Initial studies will utilize the lymphocytic choriomeningitis virus glycoprotein and nucleoprotein to investigate the mechanism of clearance of virus from neurons of the CNS and interference with differentiated cellular functions of lymphocytes and neurons. This model will be used as the groundwork for subsequent studies of human neuropathic viruses. If successful, it will generate the first transgenic expression vector for targeting expression of exogenous genes in the whole central nervous system.
