Involvement of plasminogen activator inhibitor-1 in the pathogenesis of uveitis
| Project/Area Number |
19K09924
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 56060:Ophthalmology-related
|
|---|
| Research Institution | Hokkaido University |
|---|
Principal Investigator |
Iwata Daiju 北海道大学, 大学病院, 講師 (70374402)
|
|---|
| Project Period (FY) |
2019-04-01 – 2023-03-31
|
| Project Status |
Completed (Fiscal Year 2022)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | ぶどう膜炎 / PAI－１ / 実験的自己免疫性ぶどう膜網膜炎 / EAU / PAI-1 / uveitis |
|---|
| Outline of Research at the Start |
PAI-1は線溶系の生理的阻害因子の一つと考えられている。PAI-1の増加はアテローム性動脈硬化や心筋梗塞に代表される血栓症の誘引となり、動脈硬化症や血管の再構築にも関与する。
一方でその発現はTGF-β、IL-1などの炎症性サイトカインに制御され、活性化マクロファージの遊走に不可欠なタンパクとして機能していることが明らかとなり、マクロファージ浸潤に伴う炎症と線維化に至る疾患の新たな治療標的分子として注目されている。
本研究では眼炎症疾患の動物モデル(EAUマウス)を用いてPAI-1の関与を解明し、さらに治療標的としてPAI-1阻害薬による眼炎症の軽症化について検討する。
|
| Outline of Final Research Achievements |
Plasminogen activator inhibitor (PAI) -1 has been widely accepted as the major inhibitor of endogenous fibrinolysis pathways. In addition to this role, PAI-1 has a further role in inflammatory diseases. The aim of this study is to evaluate the involvement of PAI-1 in the pathogenesis of ocular inflammation.
Firstly, we measured the protein levels of PAI-1 in vitreous samples from patients with uveitis using a magnetic multiplex bead-based quantitative immunoassay. The protein levels of PAI-1 were significantly higher in the vitreous samples of patients with uveitis than in the controls (P < 0.05). Secondly, the retinochoroidal mRNA level of PAI-1 was significantly upregulated in the EAU mice compared to the control mice (P < 0.05). Furthermore, the clinical severity of EAU was ameliorated by treatment with PAI-1 inhibitor, IMD4482 (P < 0.05). The migration of THP-1 macrophages was significantly suppressed by IMD4482.
Thus, PAI-1 has potential as a novel therapeutic target for uveitis.
|
| Academic Significance and Societal Importance of the Research Achievements |
ぶどう膜炎動物モデルEAUの網膜でのPAI-1の発現変化と病態への関与を検討し、炎症増悪とともにPAI-1の発現が亢進すること、またぶどう膜炎患者の眼局所の検体である硝子体液でPAI-1濃度が有意に高値となること、さらにPAI-1阻害薬を用いた治療でEAUの重症度の有意な低下することを初めて明らかとした。またTranswell Assayの結果からはPAI-1阻害薬による炎症抑制の背景にあるメカニズムとしてマクロファージの遊走抑制が関与している可能性を示した。
これらの結果を礎として、眼炎症の治療にこれまでと異なる分子標的からの治療スキームが我が国から誕生し、大きな社会貢献になると予測される。
|
Report
(4 results)
Research Products
(49 results)
-
-
-
-
-
-
[Journal Article] Macrophage-like iPS-derived Suppressor Cells Reduce Th1-mediated Immune Response to a Retinal Antigen.2021
Author(s)
Hase K, Namba K, Wada H, Tsuji H, Maeda A, Murata T, Otsuka R, Iwata D, Kanda A, Noda K, Kitaichi N, Seino KI, Ishida S.
-
Journal Title
Curr Eye Res.
Volume: 46
Issue: 12
Pages: 1908-1916
DOI
Related Report
Peer Reviewed
-
-
-
[Journal Article] Attenuation of experimental autoimmune uveoretinitis in mice by IKKβ inhibitor IMD-03542020
Author(s)
Liu Y, Kitaichi N, Wu D, Hase K, Satoh M, Iwata D, Namba K, Kanda A, Noda K, Itai A, Iwabuchi K, Ishida S
-
Journal Title
Biochem Biophys Res Commun
Volume: 525
Issue: 3
Pages: 589-594
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
[Presentation] ransscleral cyclophotocoagulation for ocular hypertension due to secondary intraocular lymphoma: A case report2021
Author(s)
Kanaya R, Kijima R, Kan S, Shinkai A, Kikuchi K, Yamamoto T, Iwata D, Ohguchi T, Shinmei Y, ChinS, Ishida S.
Organizer
9th World Glaucoma Cogress
Related Report
Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
