CONTRIBUTION OF AUTOIMMUNE AND INFLAMMATORY RESPONSES TO NTDS Folate homeostasis is essential for a healthy pregnancy outcome. Folic acid (FA) deficiency during pregnancy has been shown to contribute to fetal demise, growth retardation, craniofacial, cardiovascular, neural tube defects (NTDs), and numerous other congenital abnormalities. Dietary supplementation with folic acid before and during gestation markedly reduces (-70%) the incidence of NTDs in humans. Given the established role for FA in preventing NTDs, we hypothesized that dietary folate stress (i.e., a folate deficiency) may, in the presence of disrupted complement factor C5a signaling and related NO-mediated processes, have deleterious consequences for neural tube formation and closure. This is a highly novel hypothesis supported by strong preliminary evidence from our laboratory leading to the inescapable conclusion that the complement system, and in particular CD88, interacts with FA metabolism to influence neural tube closure (NTC) in murine embryos. We hypothesize that under conditions of low dietary FA, C5a generated in the developing placenta and/or developing embryo releases factors(s) that promote normal NTC, thereby preventing the development of NTDs. Clearly, under certain select conditions (infection, immune suppression, altered homocysteine homeostasis, toxicant exposure, lack of anti-oxidants, others), this regulation by C5a may not occur, and could result in the development of NTDs by previously unexamined mechanisms. This is the focus of experiments in Project 3. The proposed research will provide significant support for proposed mechanisms involving post-translational modification of selected proteins interfering with normal NTC, which opens the possibility of developing highly targeted intervention strategies that modify the impact of homocysteinylation on complement release during critical stages of development. Further dissection of the role of complement factors during NTC represents yet another potential avenue for clinical intervention in high-risk pregnancies. This has broad implications for the 300,000 infants born with NTDs annually worldwide.
This research seeks to establish the role of maternal immune factors in promoting normal embryonic neural development during gestation. We hope to better understand the interplay between nutritional factors (B vitamins) and maternal autoantibody production that can compromise normal embryonic growth and development. Understanding why some mothers produce excessive amounts of select antibodies that block nutrient transport to developing embryos will enable us to develop highly sensitive and effective intervention strategies that will help to prevent preventable birth defects.
|Leung, Kit-Yi; Pai, Yun Jin; Chen, Qiuying et al. (2017) Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure. Cell Rep 21:1795-1808|
|Chen, Xiaoli; An, Yu; Gao, Yonghui et al. (2017) Rare Deleterious PARD3 Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation. Hum Mutat 38:378-389|
|Toriyama, Manami; Toriyama, Michinori; Wallingford, John B et al. (2017) Folate-dependent methylation of septins governs ciliogenesis during neural tube closure. FASEB J 31:3622-3635|
|Akimova, Darya; Wlodarczyk, Bogdan J; Lin, Ying et al. (2017) Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate-induced neural tube closure defects. Birth Defects Res 109:106-119|
|Mauer, Jan; Luo, Xiaobing; Blanjoie, Alexandre et al. (2017) Reversible methylation of m6Am in the 5' cap controls mRNA stability. Nature 541:371-375|
|Hansler, Alex; Chen, Qiuying; Ma, Yuliang et al. (2016) Untargeted metabolite profiling reveals that nitric oxide bioynthesis is an endogenous modulator of carotenoid biosynthesis in Deinococcus radiodurans and is required for extreme ionizing radiation resistance. Arch Biochem Biophys 589:38-52|
|Denny, Kerina J; Kelly, Christina F; Kumar, Vinod et al. (2016) Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects. Birth Defects Res A Clin Mol Teratol 106:201-7|
|Lei, Yunping; Finnell, Richard H (2016) New Techniques for the Study of Neural Tube Defects. Adv Tech Biol Med 4:|
|Mitchell, Emma; Klein, Shifra L; Argyropoulos, Kimon V et al. (2016) Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms. Nat Commun 7:11492|
|Lei, Yunping; Fathe, Kristin; McCartney, Danielle et al. (2015) Rare LRP6 variants identified in spina bifida patients. Hum Mutat 36:342-9|
Showing the most recent 10 out of 40 publications