Among the severe health consequences that have been correlated with alcohol abuse are defects in myelin formation during fetal development, and demyelination during adulthood. The long term goal of the research being initiated in this proposal is to understand the cellular and molecular mechanisms underlying myelin defects that accompany alcohol abuse. Myelin is a multi-lamellar membrane which serves as an electrical insulator to facilitate neurotransmission. Defects in myelin as a result of insult or injury can dramatically affect neurotransmission. In the central nervous system (CNS), myelin is elaborated by oligodendroglial cells.
Specific Aim 1 of this proposal is to determine when in their development oligodendroglia are sensitive to ethanol, and which aspects of their development (proliferation, cell death, and/or differentiation are affected by ethanol. Oligodendroglial progenitors, pre-oligodendroglia, and mature oligodendroglia (immunoselected using antibodies to stage- specific antigens)will be cultured under control conditions or with clinically relevant levels of ethanol. The effects of ethanol exposure will be determined by assessment of cell proliferation, cell death, and differentiation. Alcohol, which has been shown to interfere with cellular responses to growth factors, may disrupt oligodendroglial responses to growth factors which regulate their proliferation and maturation, and thus, prevent myelin formation and/or maintenance.
Specific Aim 2 of this proposal is to determine if oligodendroglial responses to PDGF and IGF-1 are disrupted by ethanol exposure in vitro. Immunopanned populations of oligodendroglial progenitors, pre-oligodendroglia, and mature oligodendroglia will be cultured with PDGF or IGF-1 in the presence or absence of ethanol. Cellular responses will be evaluated as for Specific Aim 1. Experiments in Aim 2 are designed to test one possible mechanism that could underlie myelin defects that accompany exposure to alcohol, and contribute to design of therapeutic strategies to ameliorate these defects.
