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Developing a Novel Therapy through Retinal Ganglion Cell Dendrite Regeneration

Research Project

Project/Area Number 22K16961
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56060:Ophthalmology-related
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

KITAMURA Yuta  公益財団法人東京都医学総合研究所, 疾患制御研究分野, 研究員 (90868259)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords緑内障 / TrkB / AAV / 細胞死 / TrkBシグナル / 神経保護 / 網膜神経節細胞 / 樹状突起 / 軸索再生 / 遺伝子治療
Outline of Research at the Start

緑内障は進行性の視神経軸索障害に起因する神経細胞死と考えられており、一旦変性した神経細胞や軸索を再生させることは現在の治療では不可能である。我々は脳由来神経栄養因子(BDNF)の受容体であるTrkBに着目し、恒常的にBDNF-TrkBシグナル伝達を活性化する活性型TrkBのAAVベクターを作成した。視神経傷害モデルマウスの眼球に投与したところ、傷害部位を超えて多数の再生軸索が視中枢に投射し、僅かながら視機能の回復を見出している。本研究ではこの成果を発展させ、AAV-CA-TrkBベクターが視機能回復を誘導する機序を解明し、緑内障に対する新規遺伝子治療薬を開発する。

Outline of Final Research Achievements

We developed a molecule F-iTrkB that can constantly activate TrkB signaling, which successfully induced neuroprotection and axonal regeneration of retinal ganglion cells (RGCs) in optic neuropathy and normal tension glaucoma models by gene therapy using AAV2-F-iTrkB (Nishijima et al., Molecular Therapy, 2023). We also found that RGC-specific TrkB deficiency in adult mice induced relatively rapid RGC cell death, which was preceded by RGC dendrite regression, retinal function impairment and axonal degeneration. Furthermore, we found that αRGC, a subtype of RGC, most likely causes cell death due to TrkB deficiency. In addition, in order to visualize the distribution of mitochondria inside RGC dendrites with 3D images, we expressed a fluorescent protein that binds to mitochondria using AAV-vector. We found that the number of mitochondria inside dendrites was significantly reduced before RGC cell death.

Academic Significance and Societal Importance of the Research Achievements

TrkB floxマウスにAAV-Creを眼球内投与して、網膜組織中の細胞から内在性の BDNF-TrkBシグナルを消失させたところ、主にRGCの細胞死が誘導されることがわかった。 さらに、RGCの多くのサブタイプで細胞死が生じていたが、ipRGCでは比較的細胞死が抑制されていることが判明した。緑内障マウスの早期作成ができることが示唆され、今後の緑内障の研究に活用することが期待できる。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (3 results)

All 2023 Other

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Remarks (1 results)

  • [Journal Article] Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation2023

    • Author(s)
      Namekata Kazuhiko、Tsuji Naoki、Guo Xiaoli、Nishijima Euido、Honda Sari、Kitamura Yuta、Yamasaki Atsushi、Kishida Masamichi、Takeyama Jun、Ishikawa Hirokazu、Shinozaki Youichi、Kimura Atsuko、Harada Chikako、Harada Takayuki
    • Journal Title

      Cell Death Discovery

      Volume: 9 Issue: 1 Pages: 1-8

    • DOI

      10.1038/s41420-023-01460-8

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.2023

    • Author(s)
      Nishijima E, Honda S, Kitamura Y, Namekata K, Kimura A, Guo X, Azuchi Y, Harada C, Murakami A, Matsuda A, Nakano T, Parada LF, Harada T.
    • Journal Title

      Mol Ther.

      Volume: 31 Issue: 3 Pages: 810-824

    • DOI

      10.1016/j.ymthe.2022.11.018

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Remarks] 東京都医学総合研究所 視覚病態プロジェクトのホームページ

    • URL

      https://www.igakuken.or.jp/retina/

    • Related Report
      2022 Research-status Report

URL: 

Published: 2022-04-19   Modified: 2025-01-30  

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