This is a revised application for an ADAMHA Research Scientist Award. It describes in part my work as principal investigator and program director for the research program in Molecular Neurobiology and Developmental Disorders. The program consists of an administrative and scientific core serving five major investigative areas. Each area has as its central theme the application of molecular neurobiology to an understanding of developmental processes and their regulation. Studies in the Regulation of Serotonin and beta-adrenergic Receptors section (Roland D. Ciaranello, M.D., Project Director) examine the regulation of serotonin and beta- adrenergic receptor mRNA and G-protein coupling during development, as well as the regulation of these receptor mRNAs by antidepressants and drugs which alter neurotransmission. The work seeks to understand those factors which initiate and maintain receptor gene expression. The section on Enzyme Regulation (Dona L. Wong, Ph.D., Project Director) focuses on hormonal and neuronal regulation of phenylethanolamine N-methyltransferase (PNMT) gene expression during development. These studies examine differences in prenatal and postnatal mechanisms regulating enzyme expression. The section on Developmental Neurobiology of Canine Narcolepsy (William C. Dement, M.D., Ph.D., Project Director) uses an animal model of narcolepsy, an autosomal recessive disorder which afflicts young adolescents and children, to examine defects in cholinergic and alpha-1-adrenergic receptors. The research strategy utilizes the differential maturation of the relevant neurotransmitter systems to help localize the specific neurochemical lesion(s). in the section on Characterization of Developmentally Regulated Genes (John L.R. Rubenstein, M.D., Ph.D., and Roland D. Ciaranello, M.D, Project Codirectors), we are devising methods of isolating and characterizing genes which are expressed during discrete developmental epoches. We hope to identify those genes which regulate the architectural development of the cerebral cortex. Finally, the section on Molecular and Linkage Genetics of Infantile Autism (Project F, Luigi Cavalli-Sforza, M.D., Project Director) describes work seeking to find a gene marker for infantile autism in multiple-incidence families. This Research Scientist Award application describes in detail my work in the sections on receptor regulation and autism genetics.
