This proposal represents a continuation of my long-standing interest in opiate systems in the brain and their regulation. The program described here will extend my current expertise in psychopharmacology and opiate receptor characterization to the field of molecular biology in the study of the characterization, specificity, regulation and the neuroanatomical localization of the gene for a peptide acetyltransferase in rat brain with Beta-endorphin acetylating capability. Opiate systems have been implicated in mental health disorders and the acetylation of Beta-endorphin has been shown to significantly decrease its activity at the opiate receptor. Thus, acetylated Beta-endorphin may play a role in modulating human opiate systems and have implications in the pathology of these disorders. In addition, this work represents one of the first opportunities to study the regulation of peptide process enzymes at the level of the gene and opens the way for studying the possible coordinate regulation of a neuropeptide prohormone substrate, POMC, and one of its processing enzymes, the acetyltransferase enzyme. The training program described in this proposal is divided into two phases. Phase I will involve training in techniques of molecular biology including techniques for manipulating bacteria and bacteriophage cultures, quantitating, analyzing and cloning nucleic acid sequences, as well as techniques for histochemical mapping via in situ hybridization of cDNAs to mRNAs in brain and pituitary. These techniques will be applied to studying the characterization, specificity, regulation and anatomical distribution of the acetyltransferase gene in brain and pituitary. In Phase II, these techniques will be applied to the same system with a greater focus on histochemical and regulation studies.
| Hewlett, W A; Vinogradov, S; Agras, W S (1992) Clomipramine, clonazepam, and clonidine treatment of obsessive-compulsive disorder. J Clin Psychopharmacol 12:420-30 |
| Hewlett, W A; Vinogradov, S; Agras, W S (1990) Clonazepam treatment of obsessions and compulsions. J Clin Psychiatry 51:158-61 |
