ARRA: Cellular Nucleic Acid Binding Protein (CNBP) in Aging and Disease - Student Summer Research Supplemental

Investigation into the genetic causes of the muscular dystrophies has provided unique insights into the mechanisms of several disease processes. Type!! Myotonic Dystrophy is caused by a large expansion in the ZNF9 gene, which encodes the single strand RNA binding protein CNBP (Cellular Nucleic Acid Binding Protein). We recently discovered that CNBP is involved in regulating the activity of 13-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-~3 peptide (A13). The progressive fibrillization and deposition of A~ is widely believed to be the primary causal factor in the development of Alzheimer's disease (AD). This project aims to understand how CNBP regulates ~-secretase and other targets, and how its role changes with aging and disease. The requested administrative supplement for students and science educators is related to specific aims 2 and 3 of the parent grant (5R01NS058382-03). In these aims, we propose to investigate the role of CNBP in transcription and translation, and to further our understanding of its role in human disease through the investigation of tissue from both human cases and mouse models of disease. in the course of these studies, we have recently discovered that both forms of the 3-secretase enzyme (BACE1 and BACE2) are upregulated in not only AD, but in other diseases such as frontotemporal dementia (FTD). This upregulation occurs very early in the disease state, and is not driven by A~ accumulation in the brain. This summer project will build on these recent advances, while providing a valuable summer research experience for the individuals involved. This project WI]] involve experiments designed to determine the role of CNBP in these observations, using multiple techniques in cellular and molecular biology, in both tissue samples and in cultured cells. We will aim to determine (a) how CNBP changes parallel those of both BAGEl and BACE2 in human and mouse tissue, and (b) if these changes likely occur through either changes in transcription or translation. The science educator (Dr. Moshe Khurgel) and an undergraduate student (Angela Spinelli) will be drawn from Bridgewater College (Bridgewater, VA), a small (-1500 students; most of these are first generation) liberal arts college with no NIH funded research program.