My research interests are directed toward achieving a better understanding of the cellular and molecular mechanisms associated with ethanol-induced apoptosis and birth defects. Specifically, using a combination of state-of-the-art approaches, including proteomics, quantitative real-time PCR and knockout technology, my current research work is focused on the following areas: 1) ROS signaling in ethanol-induced apoptosis and birth defects; 2) Ethanol's interference with L1 cell adhesion molecule; and 3) Proteomic analysis of differential vulnerability to ethanol’s teratogenic effects. The findings from these studies may offer new strategies for development of preventative/ameliorative measures for Fetal Alcohol Spectrum Disorders (FASD).
ROS signaling in ethanol-induced apoptosis and birth defects.
Substantial evidence from our laboratory and others has suggested a major contribution of reactive oxygen species (ROS) to ethanol-induced embryonic cell injury and subsequent teratogenesis. Although many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress, the major source of ROS in ethanol-exposed embryos remains undefined. We are currently testing the hypothesis that ROS produced by NOX/DUOX family of NADPH oxidases are an important determinant of ethanol-induced apoptosis and teratogenesis. In addition, following up on our studies that have shown the ameliorative potential of exogenous antioxidants, I have initiated a study to determine the role of Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the upregulation of endogenous antioxidants in ethanol-exposed embryos.
Ethanol’s interference with L1 cell adhesion molecule
In addition to oxidative stress, alcohol appears to be damaging to a fetus as a result of interference with the L1 cell adhesion molecule (L1). In collaboration with Dr. Michael Charness at Harvard University, we have studied ethanol's interference with L1 cell adhesion molecule, as a probable mechanism underlying alcohol-related birth defects. Our studies have shown that octanol can diminish ethanol-induced apoptosis and ameliorate the adverse developmental effects of ethanol in a whole embryo culture system. This work supports the hypothesis that effects on L1 cell adhesion molecule may contribute to ethanol's teratogenicity. In addition, we have examined the antagonism of ethanol's teratogenesis by NAPVSIPQ (NAP) and SALLRSIPA (SAL), two peptide fragments of the neuroprotective proteins, that can antagonize the inhibition of L1-mediated cell-cell adhesion by ethanol. The results from this study support the hypothesis that NAP’s antagonism of ethanol’s inhibition of L1 adhesion plays a central role in its prevention of ethanol’s teratogenesis and highlight the potential importance of ethanol’s effects on L1 in the pathophysiology of FASD. We have extended this study to a recently developed maternal oral intake FASD mouse model and found that dietary D-SAL is effective in reducing the incidence of major malformations induced by ethanol exposure.
Proteomic analysis of differential vulnerability to ethanol’s teratogenic effects.
The purpose of this study is to identify and classify, using proteomics approaches, the protein networks and pathways that mediate critical events in ethanol sensitive versus non-sensitive regions of the developing mouse brain and to reveal proteins that may predispose cells to, or protect them from, ethanol-induced apoptosis. We have found a number of proteins whose expression is altered within hours of ethanol exposure. Changes in protein expression have been observed in both non-sensitive and sensitive cell populations. Identification of those proteins that are differentially expressed in control and ethanol-exposed mouse brains promises to increase our knowledge of the signaling cascades that mediate ethanol-induced apoptosis and provide insight into the selective vulnerability of certain brain regions.