University of Virginia Health System

I hold a Ph.D. (1988) in Biological Sciences from the University of Buenos Aires. I joined the Department of Neuroscience at the University of Virginia in 1997, where I am a Lecturer of Research. My research interests are in molecular and cellular mechanisms underlying growth, plasticity and aging of the nervous system. One of my research projects involves the study of the neuronal immediate early gene, Arc. Arc is a cytoskeleton-associated protein that is rapidly and transiently induced in the brain by intense neuronal activity. Soon after induction, Arc becomes selectively localized near activated postsynaptic sites where it associates with the actin cytoskeleton. Arc can to be induced using different paradigms of neuronal plasticity and it is believed to be involved in structural changes underlying activity-induced neuronal plasticity. My goal is to develop an animal model that will help to understand the role of Arc in the brain. The system is based on the use of regulatory sequences from the lac operon of E. coli. The lac operon system has been successfully used in the lab to regulate transgene expression temporally in the mouse (see Cronin et al ). To regulate Arc expression temporally and spatially, I will introduce lac operator sequences into the promoter region of the endogenous Arc gene by homologous recombination. Under normal conditions, the expression of Arc will be repressed by the lac repressor. At specific times during development, Arc will be activated with the lactose analog IPTG prior to subjecting the animal to treatments that normally induce Arc expression. These studies have the potential to help in the understanding of Arc function in the nervous system as well as the mechanisms that underlie long-term synaptic plasticity. I am also developing a transgenic mouse that can be used as a reporter for synaptic activity. The transgene consists of the promoter region of the Arc gene driving the expression of firefly luciferase, an enzyme the catalyzes the release of light photons upon oxidation of the substrate luciferin. Arc activation can be monitored in the living animal by imaging the emission of light using a highly sensitive imaging system equipped with an intensified CCD camera.

The other major focus of my work is in the understanding of the mechanisms involved in growth and aging of the brain. I am using a transgenic mouse developed in the lab that carries a mutation of the p53 gene. This mutation encodes a truncated version of p53 resulting in a protein that lacks 41 amino acids in the N terminus. Mice carrying this mutation exhibit growth retardation, reduced fertility and early death. I am looking for differences in gene expression in the brain of the p53 mutant mouse. Immunostaining of brain sections revealed differences in the expression of p27 and GFAP (Figures 1 and 2) between p53 mutant and wild type mice. By studying the phenotype of these mice, I aim to gain some understanding of the role of p53 in the development and aging of the brain.

Fig 1.

Fig 2.

Medrano S. and Steward O. (2001) Differential mRNA localization in astroglial cells in culture. J Comp. Neurol. 430: 56-71.

Medrano S. and Steward O. (1998) Differential localization of mRNAs in astroglial cells in culture. Society for Neuroscience Abstract 29.21.

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