Analysis of the innate immune receptor NOD1 as a novel cause for the development of the intrauterine fetal growth restriction

• Project/Area Number: 15K19656
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Kyushu University
• Principal Investigator: Inoue Hirosuke 九州大学, 医学研究院, 助教 (90467902)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 子宮内発育遅延 / Nod1 / 自然免疫 / 血管病変 / 胎児子宮内発育遅延 / 胎児発育遅延

Outline of Final Research Achievements

Nod1 is one of the pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. In this study, we demonstrated that administration of Nod1 ligand to pregnant mice induced IUGR and IUFD. Maternal injection of Nod1 ligand induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. CCL2 and IL-6 mRNAs were significantly induced in the fetal vascular tissues with maternal injection of Nod1 ligand than those in other tissues. Using Nod1-knockout mice, we verified that maternal Nod1 ligand directly induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface.

Research Products

• [Journal Article] An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants. (2017)
  • Author(s): Ochiai M, Kurata H, Inoue H, Tanaka K, Matsushita Y, Fujiyoshi J, Wakata Y, Kato K, Taguchi T, Takada H
  • Journal Title: Neonatology Volume: 111 Pages: 68-75
  • Peer Reviewed / Open Access
• [Journal Article] Blood Reference Intervals for Preterm Low-Birth-Weight Infants: A Multicenter Cohort Study in Japan (2016)
  • Author(s): Ochiai M, Matsushita Y, Inoue H, Kusuda T, Kang D, Ichihara K, Nakashima N, Ihara K, Ohga S, Hara T
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0161439-e0161439
  • DOI: 10.1371/journal.pone.0161439
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy. (2016)
  • Author(s): Inoue H, Nishio H, Takada H, Sakai Y, Nanishi E, Ochiai M, Onimaru M, Chen SJ, Matsui T, Hara T.
  • Journal Title: J Immunol Volume: 196 Issue: 6 Pages: 2779-87
  • DOI: 10.4049/jimmunol.1500295
  • Peer Reviewed / Open Access
• [Presentation] 出生体重500g以下児の短期予後「周産期母子医療センターネットワーク10年まとめ事業」 (2017)
  • Author(s): 井上普介
  • Organizer: 日本周産期・新生児医学会
  • Place of Presentation: 富山県富山市
  • Year and Date: 2017-07-15