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 Parkinson~s disease (PD), Huntington~s 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 AG00306-07 LCMB: Regulation of Physiological Functions During Aging: II. Neurotransmitter Responsiveness). Current studies are concentrated on transcriptional and post-transcriptional mechanisms. In addition, we are continuing to contribute to studies on the transfer of functional D2R to cell lines, rat brains and mouse brains (see project # Z01 AG00302-13 LCMB: Regulation of Physiological Functions: III. Behavioral Biology). Gen expression levels, cellular effects and behavioral consequences over time are being examined. 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 are proceeding with plans to use adenoviral vectors to deliver wildtype and mutant APP genes both to cell lines and localized areas of rat (and possibly 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.
