Developing a method to regulate intraocular pathological blood vessels by targeting AM-RAMP2 and AM2-RAMP2 systems.

• Project/Area Number: 20K09803
• 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: Shinshu University
• Principal Investigator: Shindo Yuka 信州大学, 医学部, 研究員 (50507506)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 滲出型加齢黄斑変性 / アドレノメデュリン / アドレノメデュリン2 / RAMP2 / 眼内病的血管 / RAMP / 眼内血管新生 / 網膜浮腫 / 網膜線維化

Outline of Research at the Start

本研究では、生理活性ペプチド、アドレノメデュリン(AM)と、AMのファミリーとして同定されたアドレノメデュリン2（AM2）、さらにそれらの受容体活性調節タンパクであるRAMP2の眼内における病態生理学的意義、特に網膜血管バリア維持機能、抗炎症作用、抗線維化作用とそのメカニズムを解明し、網膜浮腫や線維化に対する新たな治療法に展開することを目的とする。
糖尿病網膜症モデル、加齢黄斑変成モデルなどを用いて、AM-RAMP2系、AM2-RAMP2系各々の病態生理学的意義を明らかにする。AM-RAMP2系、AM2-RAMP2系を標的とすることで、眼内病的血管新生病に対する新しい治療法開発に展開する。

Outline of Final Research Achievements

In this study, to elucidate the pathophysiological significance of the bioactive peptides adrenomedullin (AM), adrenomedullin 2 (AM2), a member of the AM family, and their partially shared receptor activity-modifying protein, RAMP2, in neovascular age-related macular degeneration, we generated laser-induced choroidal neovascularization (LI-CNV) model using knockout mice of each.
In AM, AM2, and RAMP2 knockout mice, pathological angiogenesis was expanded and inflammation and fibrosis were exacerbated, whereas exogenous administration of AM or AM2 suppressed subretinal fibrosis by suppressing epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells.

Academic Significance and Societal Importance of the Research Achievements

滲出型加齢黄斑変性では、脈絡膜から網膜に向かって病的な脈絡膜新生血管が発生する。滲出型加齢黄斑変性における病的新生血管は構造が脆弱であり、血管透過性が高く、浮腫や出血を生じやすい。さらに血管外滲出物貯留は慢性炎症の原因となり、過剰な創傷治癒反応の結果として網膜下の線維化を生じ、これらが黄斑部に及ぶと重篤な視力障害の原因となる。
今回の研究において、AMやAM2の外因性の投与により、LI-CNVの病態が改善されたことから、両者は新たな血管制御因子として、滲出型加齢黄斑変性に対する治療標的となることが期待される。

Research Products

• [Journal Article] Receptor activity modifying protein RAMP sub-isoforms and their functional differentiation, which regulates functional diversity of adrenomedullin (2022)
  • Author(s): Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Sakurai T
  • Journal Title: Biology(Basel) Volume: 11(5) Issue: 5 Pages: 788-788
  • DOI: 10.3390/biology11050788
  • Peer Reviewed / Open Access
• [Journal Article] Adrenomedullin ameliorates pulmonary fibrosis by regulating TGF-b-Smads signaling and myofibroblast differentiation (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T
  • Journal Title: Endocrinology Volume: 162(8) Issue: 8 Pages: 1-22
  • DOI: 10.1210/endocr/bqab090
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T
  • Journal Title: Endocrinology Volume: 162(3) Issue: 3 Pages: 0-0
  • DOI: 10.1210/endocr/bqab001
  • Peer Reviewed
• [Journal Article] Adrenomedullin-receptor activity-modifying protein 2 system ameliorates subretinal fibrosis by suppressing epithelial-mesenchymal transition in age-related macular degeneration (2021)
  • Author(s): Tanaka M, Kakihara S, Hirabayashi K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Aruga K, Yamauchi A, Murata T, Shindo T
  • Journal Title: Am J Pathol Volume: 191(4) Issue: 4 Pages: 652-668
  • DOI: 10.1016/j.ajpath.2020.12.012
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 system ameliorates pulmonary fibrosis by regulating TGF-β-Smads pathway and differentiation of myofibroblasts. (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui1 N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shind T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts (2020)
  • Author(s): Dai K, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Matsui S, Shindo T
  • Journal Title: Oncogene Volume: 39(9) Issue: 9 Pages: 1914-1930
  • DOI: 10.1038/s41388-019-1112-z
  • Peer Reviewed
• [Presentation] アドレノメデュリン２はヒト網膜色素上皮細胞の上皮間葉転換を抑制する (2022)
  • Author(s): 柿原伸次、松田順繁、平林一貴、今井章、鳥山佑一、家里康弘、桜井敬之、神吉昭子、田中愛、新藤優佳、河手久香、村田敏規、新藤隆行
  • Organizer: 第126回 日本眼科学会
• [Presentation] Transcriptome analysis of the pathophysiological significance of adrenomedullin 2 in the mouse choroidal neovascularization model. (2022)
  • Author(s): Kakihara K, Sakurai T, Kamiyoshi A, Tanaka M, Kawate H, Ichikawa-Shindo Y, Zhao Y, Matsuda Y, Hirabayashi K, Imai A, Iesato Y, Murata T, Shindo T.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2022
  • Int'l Joint Research
• [Presentation] Adrenomedullin-2 ameliorates neovascular AMD via the upregulation of Meox2 (2022)
  • Author(s): Kakihara S, Matsuda Y, Hirabayashi K, Imai A, Iesato Y, Sakurai T, Kamiyoshi A, Tanaka M, Ichikawa-Shindo Y, Kawate H, Murata T, Shindo T
  • Organizer: 第61回日本網膜硝子体学会
• [Presentation] Adrenomedullin-2/intermedin ameliorates pathological angiogenesis and associated inflammation and fibroticlesions via Meox2. (2022)
  • Author(s): Kakihara S, Matsuda Y, Sakurai T, Kamiyoshi K, Tanaka M, Ichikawa-Shindo Y, Kawate H, Zhao Y, Zhang Y, Guo Q, Li P, Onishi N, Kasahara T, Shindo T.
  • Organizer: 第87回日本循環器学会
• [Presentation] 加齢黄斑変性および未熟児網膜症におけるアドレノメデュリン2の病態生理学的意義 (2021)
  • Author(s): 柿原伸次、田中正明、平林一貴、今井章、鳥山佑一、家里康弘、桜井敬之、神吉昭子、新藤優佳、河手久香、田中愛、村田敏規、新藤隆行
  • Organizer: 第125回日本眼科学会
• [Presentation] Pathophysiological roles of adrenomedullin-2 in mouse model of ocular neovascularization. (2021)
  • Author(s): Kakihara S, Tanaka M, Hirabayash K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Kawate H, Ichikawa-Shindo Y, Tanaka M, Murata T, Shindo T.
  • Organizer: The Association for Research in Vision and Ophthalmology 2021
• [Presentation] 眼内血管新生病におけるアドレノメデュリン２の病態生理学的意義 (2021)
  • Author(s): 柿原伸次、田中正明、平林一貴、今井章、鳥山佑一、家里康弘、桜井敬之、神吉昭子、新藤優佳、河手久香、田中愛、崔南奇、Wei Yangxuan、Zhao Yunlu、有賀公亮、笠原智貴、村田敏規、新藤隆行
  • Organizer: 第50回日本心脈管作動物質学会
• [Presentation] Adrenomedullin-RAMP2 system regulates vascular endothelial homeostasis, which suppresses hematogenous and lymphogenous metastasis. (2021)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 system ameliorates age-related macular degeneration by suppressing choroidal neovascularization and subretinal fibrosis. (2021)
  • Author(s): Tanaka M, Kakihara S, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/