The mechanisms of tissue injury in the setting of chronic alcoholism and developmental abnormalities associated with fetal alcohol syndrome are unknown. However, alcohol-induced tissue injury is generally associated with isolated cell loss that is characteristic of programmed cell death, apoptosis, rather than necrotizing forms of injury. In this regard, we have recently demonstrated that ethanol markedly sensitizes cells to apoptosis by suppressing the tyrosine kinase activity of the insulin-like growth factor I receptor (IGF-IR), a receptor that is key to the survival of many cell types. We hypothesize that ethanol-induced toxicity is modulated, at least in part, by expression and activation of the IGF-IR. Murine fibroblasts and neuroglial cell lines that exhibit tight growth factor regulation, IGF-I in particular, will be used as in vitro models to test the effect of ethanol on various modes of apoptosis initiation. The enhancement of apoptosis by ethanol will be correlated with IGF-IR expression and tyrosine auto-phosphorylation, and the expression and activation of key proximal signal mediators such as insulin-related substrate-1 (IRS-1), Src-homology 2/alpha-collagen (Shc), and phosphatidyl inositol 3-kinase. The effect of ethanol on IGF-IR and apoptosis will then be studied in rodent and chicken primary neuronal cell cultures and in vivo models. Specifically, we will analyze ethanol effects on the developing chicken, an established model for fetal alcohol syndrome, and relate neural crest cell death to the developmental dynamics of IGF-IR expression. Cell death will also be studied using implantable biodiffusion chamber in ethanol-intoxicated mice. Finally, we will use a novel functional expression cloning approach to identify IGF-I-inducible survival genes. We will study the effect of ethanol of the expression of these genes, and determine whether the overexpression of the genes desensitizes cells to the pro-apoptotic effect of ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA007186-15
Application #
6200874
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
15
Fiscal Year
2000
Total Cost
$130,719
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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