Neural tube defects (NTDs) are the second most common serious birth defect, with an estimated prevalence of 1 in 2,000 pregnancies in the US annually. NTDs arise from a complex interplay of multiple genes and environmental exposures. One of the best-known but still poorly understood means of reducing NTD rates is increasing prenatal folic acid (FA) intake. In human populations, dietary FA supplementation can prevent up to 70% of NTD occurrences-including anencephaly and spina bifida?by as yet unknown mechanism(s). The current clinical practice of FA supplementation is based on epidemiological data indicating broad benefit and presumed little or no detriment. In contrast to conventional wisdom, our recent data in the mouse indicate that even moderate levels of FA supplementation that are protective against NTD in one mutant mouse line can increase embryopathy in another line, suggesting that FA works through multiple mechanisms depending on as yet unknown genetic factors, not all of which are protective to the developing embryo. Clearly, families would be far better served if their individual risks could be accurately assessed, including identification of which aspect of the FA pathway~or supplement involving another pathway entirely-would provide the most benefit to them, so that NTD prevention strategies could be optimized according to individual genetic risk factors. Our goal is to help improve NTD risk assessment and prevention by integrating advanced human genomics with biological paradigms in humans and mice for identifying key gene-environment interactions. Project 1 (Ross &Musser, Pis) will use nanotechnology-assisted deep resequencing to discover rare variants in human genes?and allele interactions-that enhance NTD risk. For some prominent identified risk genes, we will also test whether the variant alleles increase NTD risk via functional interaction with gene networks that contribute to Wnt signaling, folate metabolism or oxidative/nitrosative stress. Project 2 (Gross PI) will definitively test, in mice, the hypothesis that nitric oxide insufficiency and oxidative/nitrosative stress are major contributors to NTD risk in genetically predisposed embryos. State-ofthe- art metabolite profiling technologies will be used to broadly discover NTD-associated perturbations in small molecule levels and metabolic pathway activities. These studies seek to identify small molecules that can further reduce NTD risk when administered with folate as a maternal supplement. Project 3 (Finnell PI) will examine the interaction of folate metabolism and inflammatory responses in the genesis of NTDs. Studies will use genetically modified mice to study the post-translational modification of critical developmentally-regulated proteins that are likely to be modified by nutritional status, genetic background and generation of reactive oxidative species that render embryos highly susceptible to NTDs. The three highly integrated projects will define patterns of genetic and environmental conditions that can increase NTD risk in humans and may provide new insights for NTD prevention.
This Program will provide the most comprehensive translational information to date toward the understanding of human NTD risk and prevention. It could also serve as a model strategy for investigating the involvement of FA metabolism and oxidative stress in other diseases, including complex genetic disorders such as autism and schizophrenia, thought to be subject to gene-environment interactions.
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