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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08NS001330-04
Application #
3084269
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037