My research focuses on the regulation of gene expression in the CNS, with an emphasis on two genes whose protein products play important roles in excitotoxic neuronal cell death.

Glutamine synthetase (GS) is expressed at high levels in certain glial cells where it metabolizes and inactivates the neurotransmitter (and excitotoxin) glutamic acid. My laboratory aims to understand the molecular mechanisms leading to a high level of GS expression in glial cells, using the embryonic chicken retina as a model system.

We have cloned and characterized the chicken GS gene and are presently identifying genetic elements important for its expression in retinal MÙller glial cells. Our research has established that retinal primary cultures and, more surprisingly, intact retinal organ cultures are amenable to the expeditious methods of gene transfer and analysis routinely used to characterize genetic control elements in continuous cell lines. Moreover, we have developed an assay system to identify the elements important for MÙller cell specific expression of GS. Current efforts are focused on relating the functioning of various control elements to the regulation of GS gene expression during retinal development, and to identify protein transcription factors that guide this process.

Nitric oxide synthesized by neuronal nitric oxide synthase (NOS1) is an important mediator of excitotoxic neuronal cell death. With an eye toward future pharmacologic intervention, our laboratory is attempting to elucidate the physiologically relevant modes of transcriptional control of the human NOS1 gene.

We have discovered that NOS1 mRNAs with different 5' terminal exons are transcribed in the CNS. Moreover, a novel genetic structure, involving closely linked but separable promoters, is responsible for this effect. Current efforts are focused on the development and analysis of cell culture and transgenic mouse based systems; in order to study human NOS1 promoter function in developing, regenerating, and traumatized neurons.