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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-N)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
New York
United States
Zip Code
Lei, Yunping; Fathe, Kristin; McCartney, Danielle et al. (2015) Rare LRP6 variants identified in spina bifida patients. Hum Mutat 36:342-9
Tsurubuchi, Takao; Allender, Elise V; Siddiqui, M Rizwan et al. (2014) A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 -/- embryos. Childs Nerv Syst 30:1343-53
Hansler, Alex; Chen, Qiuying; Gray, Jason D et al. (2014) Untargeted metabolite profiling of murine embryos to reveal metabolic perturbations associated with neural tube closure defects. Birth Defects Res A Clin Mol Teratol 100:623-32
Diani-Moore, Silvia; Ma, Yuliang; Gross, Steven S et al. (2014) Increases in levels of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EETs and DHETs) in liver and heart in vivo by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in hepatic EET:DHET ratios by cotreatment with TCDD and the soluble epoxide hydrolas Drug Metab Dispos 42:294-300
Lei, Yunping; Zhu, Huiping; Yang, Wei et al. (2014) Identification of novel CELSR1 mutations in spina bifida. PLoS One 9:e92207
Fathe, Kristin; Palacios, Ana; Finnell, Richard H (2014) Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol 100:592-7
Ismailoglu, Ismail; Chen, Qiuying; Popowski, Melissa et al. (2014) Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol 391:230-40
Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L et al. (2014) KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability. Sci Signal 7:ra22
Wallingford, John B; Niswander, Lee A; Shaw, Gary M et al. (2013) The continuing challenge of understanding, preventing, and treating neural tube defects. Science 339:1222002
Denny, Kerina J; Jeanes, Angela; Fathe, Kristin et al. (2013) Neural tube defects, folate, and immune modulation. Birth Defects Res A Clin Mol Teratol 97:602-9

Showing the most recent 10 out of 21 publications