The focus of our work is on the function and regulation of genes whose expression changes with aging and/or neurodegenerative disease. We have chosen to study regulation of the D2 dopamine receptor (D2R) gene because of its demonstrated and suspected roles in the decrease in motor abilities associated with normal aging as well as neurodegenerative diseases such as Parkinsons disease (PD), Huntingtons disease (HD), and tardive dyskinesia. This project is a natural extension and refinement of work on the loss of D2 receptors and mRNA with aging (see project # Z01-AG00306-6 LCMB: Regulation of Physiological Functions During Aging: II. Neurotransmitter Responsiveness). In addition, we are continuing to contribute to studies on the transfer of functional D2R to rat brain and any resulting cellular and behavioral effects (see project # Z01-AG00302-12 LCMB: Regulation of Physiological Functions: III. Behavioral Biology). We are also investigating regulation of the amyloid precursor protein (APP) gene because of the demonstrated and suspected roles that it plays in the neuropathology and etiology of Alzheimer's disease (AD), Down's syndrome (DS), and normal brain aging. Finally, as a result of an internal competition to identify new and important collaborative projects within the GRC, we have received support from the Acting Scientific Director to proceed with our plans to use adenoviral vectors to deliver wildtype and mutant APP genes to localized areas of rat (and/or monkey) brain in order to study expression, processing and normal function of the APP gene products, as well as to possibly reproduce the pathology and/or behavioral changes associated with AD in an animal model
