Calmodulin-Dependent Enzymes; Molecular Neurobiology; Neurotoxicology

There are three major research interests in this laboratory. One area of active investigation involves mechanisms of calcium-induced signal transduction in brain, focusing on calmodulin-mediated enzymes. We have focused attention on the regulation of calmodulin-dependent protein phosphatase, and calcineurin. The role of phosphatases in cellular regulation is emerging as an exciting area of research, with implications for cell growth, signaling, and immune system regulation. We have found that calcineurin interacts with Bcl-2, and this interaction may play a role in apoptosis. Current attention is focused on identification of substrates for calcineurin, with an emphasis on cytoskeletal proteins, such as tau protein, which is highly phosphorylated in Alzheimer's disease. We have developed several in vitro and in vivo transgenic approaches for determination of changes in neuronal function caused by expression of specific tau mutant forms.

The second major area of the lab is the isolation and characterization of novel, neuron-specific genes, with emphasis on those involved in neurotoxic actions of various agents. We have used subtractive hybridization techniques coupled with selective neuronal ablation via neurotoxicant treatment to isolate gene products that are enriched in neurons sensitive to various toxicants. This approach has been applied towards understanding the molecular basis for the selective nature of organotin toxicity and has resulted in the isolation and sequencing of a novel cDNA, which may encode a protein involved in the molecular basis of neurotoxicity. The protein encoded by this cDNA has been identified and named stannin. We have found that stannin expressed in selective cells, and that it is located on human and mouse chromosome 16. This highly conserved protein may induce apoptosis via interactions with other proteins.

The third focus of my activities is the supervision of the Core Facilities at Penn State, College of Medicine. These labs provide state-of-the-art facilities for protein and DNA sequencing, Peptide and DNA synthesis, image analysis, and production of transgenic animals for disease models. These services are available for use on student thesis research projects and by faculty.