Response Signatures of Alcohol-Related Birth Defects

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DESCRIPTION (provided by applicant): Maternal alcohol use during pregnancy is a significant public health problem. It affects 1% infants and is the leading preventable cause of mental retardation. This project addresses the mechanisms of target organ susceptibility to prenatal alcohol exposure. Eye defects such as coloboma, microphthalmia and optic nerve hypoplasia are a cardinal feature of the Fetal Alcohol Syndrome (FAS) and reflect lesions induced by maternal alcohol exposure during early development. Our hypothesis states that mitochondria react to alcohol-induced oxidative stress by invoking a conserved checkpoint for developmental plasticity. The checkpoint fine-tunes cellular remodeling, but may disrupt morphogenetic remodeling under stressful conditions. The signal is started by the mitochondrial Bzrp/TspO protein, an oxygen-sensing signal generator and recasts signaling networks. Receptor-mediated cell adhesion pathways appear most sensitive; as such, mitochondria intercept the flow of molecular regulatory information between nucleus and cell surface. Preliminary studies show that the C57BL/6J background (B6J) is at high risk for alcohol-induced eye defects whereas the C57BL/6N background (B6N) carries a low risk. B6J embryos are protected from alcohol-related eye defects with PK11195, a potent pharmacological ligand for Bzrp/TspO. Specific Aim 1 will determine if genetic predisposition to PK11195-responsive eye defects is linked to the maternal disposition for Fetal Alcohol Syndrome in pregnant mice. Specific Aim 2 will establish a causal link between Bzrp/TspO and alcohol-induced eye defects using genetic (B6J, B6N), pharmacological (PK11195), and molecular (antisense) manipulation in whole embryo culture. Specific Aim 3 will identify microRNA (miRNA) signatures for receptor-mediated cell adhesion systems altered during the pathogenesis of alcohol-induced eye defects. Specific Aim 4 will sustain 'Birth Defects Systems Manager' (BDSM) as an ongoing bioinformatics-knowledge management system to enable secondary analysis of relevant developmental and genomic data. Achieving these Specific Aims will lead to a better understanding of the disease risks associated with maternal alcohol consumption and can advance new diagnostics for individual susceptibility to alcohol-related birth defects in general and pediatric ophthalmic disorders in particular.