Excitotoxic cell death is thought to be a central and underlying cause of brain damage in a variety of neurodegenerative disorders and results from overproduction or accumulation of excitatory amino acids. Our long-term objectives are to delineate the dual roles of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway in the regulation of both neuroprotection and excitotoxic cell death. Our laboratory investigates signal transduction pathways involved in serotonin-mediated neuroprotection and kainate-induced excitotoxic cell death. Currently, we have mutants of the striatal-enriched tyrosine phosphatase (STEP) which have been fused to the HIV TAT Peptide. These TAT-STEP fusion proteins bind to ERKs, prevent ERK nuclear translocation, and regulate the duration that ERKs are active. We have shown that these TAT-STEP fusion proteins readily enter primary cell cultures, bind to ERK, and prevent nuclear signaling. The specific aims of our laboratory are to utilize these TAT-STEP fusion proteins to: 1) delineate the early vs. late roles of ERK in neuroprotection and/or cell death, 2) determine the involvement of downstream effector molecules, particularly Fos and CREB, in ERK-mediated excitotoxic cell death, 3) identify mechanisms of neurodegeneration by characterizing the effects of the TAT-STEP fusions on excitotoxin-mediated cell death pathways, particularly the regulation of Bcl-2 family members by ERK, and 4) determine whether TAT-STEPs are neuroprotective in an in vivo seizure model. Identification of specific pathways separating ERK-mediated survival vs. death will enable more selective therapeutic intervention in neurodegenerative disease by permitting the selective interference of cell death pathways, while maintaining the neuroprotective role of ERK, in order to minimize or reverse neurological damage resulting from excitotoxic insult.

A second objective has been to enhance our understanding of signal transduction in both brain and cancer cells through identification and functional delineation of novel signal transduction molecules. Our focus has been on the identification and characterization of signaling molecules with the expectation that, in addition to gaining insight into brain function, subtle alterations in the function of such molecules and their concomitant signaling pathways will be identified as the underlying cause of specific oncological, neurological, and psychiatric diseases. To this end, we have developed a novel cDNA screening system to identify genes capable of causing transcriptional activation of the human c-fos promoter. Using this screen, we have identified two genes, denoted CROC-1 and CROC-4, and are examining their role in neuronal differentiation and cancer.

Publications

Courses taught by Dr. Lin: Neuropharmacology (BIOL324/524), Laboratory in Cellular and Molecular Neurobiology (BIOL250)

Turner BioSystems - Fluorometer Grants Program http://www.fluorometer-grants.org