9311307 Sherman Vasopressin is a peptide hormone that is synthesized in magnocellular neurons of the hypothalamus and is secreted into the blood stream from nerve endings in the posterior pituitary. The primary stimulus for vasopressin release by the posterior pituitary is dehydration. Indeed, this neuropeptide is the antidiuretic hormone. It is essential for the regulation of water balance. In addition, vasopressin is involved in stress mechanisms since it acts synergistically with the hypothalamic- pituitary-adrenal axis to stimulate secretion of adrenocorticotropic hormone. Much of our knowledge about vasopressin has resulted from work with the Brattleboro rat. These rats do not synthesize vasopressin because of a single base deletion in the gene which is inherited as an autosomal recessive trait. As a consequence of this gene defect, Brattleboro rats develop diabetes insipidus. Dr. Sherman is examining the use of a modified herpes virus to facilitate in vivo investigations of vasopressin structure- function relationships. The herpes virus type 1 (HSV-1) is uniquely capable of infecting non-dividing cells, such as neurons. Moreover, it has the added characteristic of existing in neurons, under some conditions, in a dormant or quiescent state termed latency, during which only a small portion of the herpes genome is active. Using newly developed state-of-the-art techniques, Dr. Sherman will engineer a special modified HSV-1 virus to incorporate a working version of the gene for vasopressin. He will develop different versions of normal vasopressin gene constructions and various HSV-1 viral modifications to maximize the expression of normal vasopressin hormone in Br attleboro rats. Results from this work are likely to make significant contributions both within the field of vasopressin research and the development and use of HSV vectors for gene expression. Indeed, the ultimate goal is to correct the diabetes insipidus defect by specifically targeting magnocellular neurons by direct injections of the vasopressin-containing virus into the posterior pituitary, where the virus particles can be taken up by the magnocellular nerve terminals, retrogradely transported to the hypothalamic cell bodies, establish latency, and begin expressing the virally-contained vasopressin gene. This work provides an important bridge between neuroscience and virology and leads the way for new developments in gene therapy. ***
