Fetal alcohol syndrome (FAS) refers to a recognized pattern of birth defects that occurs in a subset of children born to women who consume alcohol during pregnancy. Typical alcohol- related birth defects include microencephaly, microphthalmia, deficiencies of the facial prominences and visceral arches, as well as effects on the heart, great vessels, and thymus. Understanding disease mechanisms in prenatal alcohol exposure depends upon learning what metabolic and regulatory pathways mediate critical steps leading to dysmorphogenesis. The research proposed here uses gene expression arrays and bioinformatics to probe the origins of alcohol-related birth defects in an acute animal model. Many disease endpoints in human alcohol-related birth defects can be induced acutely in C57BL/6J mice during gastrulation-neurulation phases of development.
Specific Aim 1 will survey the normal (developmental) gene expression for structures commonly malformed in alcohol-related birth defects. Parameterization will landmark key stages of ocular and hindbrain development across the window of vulnerability to ethanol-induced teratogenesis (days 8-10 of gestation) using C7BL/6J and CD-1 strains of mice that are differentially responsive to acute gestational exposure of ethanol. Conventional microdissection and laser capure microdissection will isolate specific precursor target cell populations from the test and reference samples.
Specific Aim 2 will enumerate alcohol-related changes of gene expression within the exposure-disease continuum. Parameterization will entail dose-response, time after exposure, and strains differing in sensitivity. Emphasis will be the developing eye and hindbrain for exposure on day 9 of gestation.
Specific Aim 3 is to initiate a functional genomics/computational biology pipeline for comprehensive pattern recognition, exploration, and validation of alcohol-related changes in developing target organs. Microarray data will be amalgamated into the first gene expression reference database for detecting alcohol-related effects on the developing embryo. This effort will enable computation of critical response signatures that represent core phenomena in disease mechanisms. By studying multigenic response signatures we hope to define the various metabolic and regulatory pathways set into disarray during critical periods of prenatal ethanol exposure. At ends, we expect this knowledge will enable researchers to identify mechanisms of alcohol-related birth defects and noninvasive strategies toward intervention. Project-generated resources will include the design and construction of specialized arrays focused on the genes emerging as responsive to ethanol intoxication, as well as a relational database made accessible to the scientific community through the world-wide web.
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