Elucidation of the molecular mechanism and development of therapeutic strategies for the sphingolipid-mediated pregnancy loss
| Project/Area Number |
15K09711
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Embryonic/Neonatal medicine
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2015-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | スフィンゴ脂質 / 妊娠 / 不育症 / 自然免疫 / 好中球細胞外トラップ / 胎児医学 |
|---|
| Outline of Final Research Achievements |
Exaggerated maternal immune responses must be strictly controlled to ensure a successful pregnancy. In this study, we demonstrated that Neutrophil extracellular traps (NETs) play a key role in the pathogenesis of sphingosine kinase (Sphk)-mediated pregnancy loss. Perturbing the sphingolipid pathway by disrupting Sphk genes during pregnancy led to excessive NET formation exclusively at the fetomaternal interface and early fetal death. Neutrophils that formed NETs were characterized by histone hypercitrullination and peptidylarginine deiminase 4 (PAD4) overexpression. Blocking NET formation with a PAD4 inhibitor protected Sphk -deficient mice from pregnancy loss. Moreover, NET formation was induced in human neutrophils stimulated with Sphk-deficient human decidual cells. Together, these findings indicate that targeting NETs might be a novel therapeutic strategy to treat idiopathic pregnancy loss in humans.
|
| Academic Significance and Societal Importance of the Research Achievements |
不育症には原因不明で、難治性のものが多い。難治性不育症については、確立された治療法が全くないのが現状である。ヒトの不育症研究では、患者の血清/血漿を用いた研究が多く、検出された異常が原因か結果であるかを判断するのが難しい。現在、原因不明の不育症に対する免疫グロブリン療法が国内で多施設共同の臨床試験として行われている。免疫グロブリン療法を用いた臨床試験は世界でも行われているが、その有効性についてはまだ議論が分かれている。不育症モデルマウスを用いた私の研究は、不育症の原因解明・治療法開発に有用であり、ヒトへの応用に向けた未来に大きく道を開くものであると考える。
|
Report
(5 results)
Research Products
(5 results)
