Role of sphingosine 1-phosphate 3 signaling in choroidal neovascularization and fibrosis.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16879
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: IWANISH HIROKI 和歌山県立医科大学, 医学部, 准教授 (40784319)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: スフィンゴシン-1-リン酸 / レーザー誘発脈絡膜新生血管 / TGFb / 創傷治癒 / 滲出型加齢黄斑変性

Outline of Final Research Achievements

Laser-induced choroidal neovascularization (CNV) was significantly suppressed in S1P3-deficient mice, and the expression of inflammatory cytokines, including TGFb, was decreased in laser-irradiated tissues. There was no significant difference in laser-induced CNV after reciprocal bone marrow transplantation between S1P3-deficient and wild-type mice. Immunostaining showed increased expression of S1P2 in laser-induced CNV tissue from S1P3-deficient mice.
Systemic administration of an S1P2 selective inhibitor to S1P3-deficient mice did not enhance neovascular suppression. In vitro tube formation assays also showed no additional effect of S1P2 inhibition on lumen formation in response to S1P3 inhibition.

Free Research Field

眼創傷治癒

Academic Significance and Societal Importance of the Research Achievements

加齢黄斑変性は先進国中途失明原因の上位疾患である。滲出型加齢黄斑変性に対して臨床的に抗VEGF抗体の硝子体内注射が有効であるが、一度退縮した新生血管の再燃による繰り返し投与とそれに伴う高額な医療費、治療中の線維瘢痕化に伴う不可逆的視力障害などの課題がある。
本研究で、マウスモデルで滲出型加齢黄斑変性における新生血管へのS1P受容体レベルでの関与を証明した。S1P3シグナル抑制によるTGFbシグナルの抑制も認めた。シグナル補完に関しては、血管新生抑制に関してS1P2とS1P3同時阻害による追加作用はなかった。S1P3シグナル単独抑制が滲出型加齢黄斑変性の新たな治療ターゲットになり得ると結論付けた。