Maternal alcohol consumption during pregnancy can adversely affect T-cell function in the offspring. This has been demonstrated in both man and animals. T-cell differentiation occurs in the thymus and involves interactions with regulatory factors produced by thymic stromal cells. It is proposed that prenatal exposure to alcohol and/or alcohol induced changes in maternal hormones induce a permanent change in expression of one or more of the stromal factors required for normal T-cell maturation, resulting in an immunosuppressive """"""""imprinting"""""""" of the fetus. Thus, the overall goal of the proposal is to identify the genes encoding these factors, and determine their role in prenatal alcohol-induced immunosuppression. The strategy for identifying these genes is based upon previously described observations that maternal adrenalectomy reverses the T-cell dysfunction observed in fetal alcohol-exposed male rats. Therefore, this proposal will examine the developing fetal thymus for changes in gene expression brought about by FAE and maternal adrenalectomy.
The specific aims are: 1) to analyze expression of known candidate genes in the fetal thymic stromal and lymphoid compartments that may contribute to FAE-induced T-cell dysfunction. 2) Identify new genes with altered expression of fetal thymic stromal cells due to FAE. 3) Establish a fetal thymic cell culture model of FAE. 4) Manipulate expression of specific genes in the fetal thymic cell culture model. Expression of genes identified in experiments 1 and 2 will be manipulated using antisense oligonucleotides to inhibit their expression, or expression vectors to overexpress these genes. Thus, a causal relationship may be established between altered expression of these genes and the observed changes in thymocyte differentiation in response to FAE.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AA011580-02
Application #
2769225
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Project Start
1997-09-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611