Ethanol is a known human teratogen of immense public health impact. Heavy drinking during pregnancy is the leading known cause of mental retardation, while more subtle effects particularly on the developing brain occur in 1% of all liveborns. Recent evidence has shown that many of the known protein targets for ethanol's toxic effects on the developing central nervous system are associated with lipid rafts. Lipid rafts are specialized microdomains of the plasma membrane and serve as platforms for protein-protein interactions. Our prior work has shown that the ability of L1 cell adhesion molecule (L1), a protein critical for the proper development of the nervous system, to promote neurite outgrowth is exquisitely sensitive to ethanol. Localized disruption of lipid rafts reduces L1 mediated neurite outgrowth. Our preliminary data show that ethanol alters the distribution of L1 in lipid rafts, and that cholesterol depletion abolishes ethanol sensitivity. Further, our preliminary data suggests that other protein targets of ethanol change their lipid raft distribution in the presence of ethanol. We hypothesize that a major mechanism of ethanol toxicity is through alteration of lipid raft-protein interactions, and that interventions which reduce toxicity prevent this disruption. These hypotheses will be tested using cerebellar granule neurons (CGN) from rat pups and from mice, both wild type and lacking L1, and a rat in vivo entubation model.
In Aim 1, we will confirm that lipid raft-L1 interactions underlie ethanol sensitivity of neurite outgrowth by transfecting CGN lacking L1 with mutant constructs of L1 lacking a signal to colocalize with lipid rafts. Neurite outgrowth in transfected cells is expected to be ethanol insensitive.
In Aim 2, we will determine whether L1 or the lipid raft is the site of the ethanol action, and the effect of ethanol on the kinetics of L1 trafficking to and out of the lipid raft compartment.
In Aim 3, we will use four nutrients shown to be protective in other experimental systems, to prevent the changes in protein distribution secondary to ethanol. The most effective combination of these nutrients will be determined with L1 in CGN and in the in vivo model. The relevance of this research is that simple dietary manipulations with these nutrients may prevent some aspects of ethanol neurotoxicity much like folic acid supplementation and reduction of neural tube defects.
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