Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

Ikeda, Shin‐ichi; Kurihara, Toshihide; Jiang, Xiaoyan; Miwa, Yukihiro; Lee, Deokho; Serizawa, Naho; Jeong, Heonuk; Mori, Kiwako; Katada, Yusaku; Kunimi, Hiromitsu; Ozawa, Nobuhiro; Shoda, Chiho; Ibuki, Mari; Negishi, Kazuno; Torii, Hidemasa; Ohta, Michio

doi:10.1038/s41467-022-33605-1

Cited by 20 publications

(24 citation statements)

References 49 publications

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“…The most common animal models of myopia are form-deprivation myopia (FDM) and lens-induced myopia (LIM) [ 2 – 4 ]. Recently, our team found that mice with LIM showed endoplasmic reticulum (ER) stress in the sclera, which is similar to the results of other researchers using the FDM model [ 5 , 6 ]. Furthermore, we previously showed that scleral ER stress causes myopia [ 5 , 6 ].…”

Section: Introductionsupporting

confidence: 86%

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Establishment of a novel ER-stress induced myopia model in mice

Kang,

Ikeda,

Yang

et al. 2023

Eye and Vis

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Background Recent studies have indicated a strong correlation between endoplasmic reticulum (ER) stress and myopia and that eyedrops containing the ER stress inducer tunicamycin (Tm) can induce myopic changes in C57BL/6 J mice. Therefore, this study aimed to create a new myopia model using Tm eyedrops and to explore the mechanism of ER stress-mediated myopia development. Methods Three-week-old C57BL/6 J mice were treated with different concentrations (0, 25, 50, and 100 μg/mL) and/or number of applications (zero, one, three, and seven) of Tm eyedrops. Refraction and axial length (AL) were measured before and one week after Tm treatment. Scleral collagen alterations were evaluated under polarised light after picrosirius red staining. ER stress-related indicators, such as the expression of collagen I and cleaved collagen were detected using Western blotting. Results Compared with the control group, mice administered eyedrops with 50 μg/mL Tm only once showed the greatest myopic shifts in refraction and AL elongation and reduced scleral expression of collagen I. Picrosirius red staining showed a lower percentage of bundled collagen in the Tm group. Expression of ER-stress indicators increased in the Tm groups. Furthermore, optimised administration of Tm induced matrix metalloproteinase-2 (MMP2) expression in the sclera, which plays a major role in collagen degradation. Conclusions We have demonstrated that ER stress in the sclera is involved in myopia progression. Tm eyedrops induced myopic changes, loosening of the scleral collagen and decreased expression of collagen I. This process may be associated with ER stress in the sclera, which upregulates the expression of MMP2 leading to collagen degradation.

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Section: Introductionsupporting

confidence: 86%

“…Recently, our team found that mice with LIM showed endoplasmic reticulum (ER) stress in the sclera, which is similar to the results of other researchers using the FDM model [ 5 , 6 ]. Furthermore, we previously showed that scleral ER stress causes myopia [ 5 , 6 ]. This clearly indicates a correlation between myopia and ER stress.…”

Section: Introductionsupporting

confidence: 86%

Establishment of a novel ER-stress induced myopia model in mice

Kang,

Ikeda,

Yang

et al. 2023

Eye and Vis

Self Cite

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“…Recent studies have indicated that hypoxia might be one of the key mechanisms inducing abnormal ECM remodeling in the regulation of scleral ECM during myopia (Wu et al 2018 ). Additionally, our previous findings demonstrated that endoplasmic reticulum stress in the sclera might play a significant role in the expression of ECM proteins (Ikeda et al 2022 ). However, due to the intricate composition of the ECM, elucidating the role of specific ECM genes in the myopia process is challenging, and further exploration of the associated mechanisms is warranted.…”

Section: Discussionmentioning

confidence: 97%

“…SaCas9 or guide RNA (Supplementary Table T2 ) against THBS1 expression cassettes were constructed and packaged into AAV-DJ vectors (titer > 1.0E + 13 GC/ml) by Vector Builder as described in previous reports (Ikeda et al 2022 ; Zhao et al 2018 ). The mice were randomly assigned to three groups: a sham-operation group (anaesthetized and had a ‘dry’ needle inserted with no injection), a group injected with scramble guide RNA, and a group injected with gThbs1.…”

Section: Methodsmentioning

confidence: 99%

“…A 1:1 mixture of AAV-packaged SaCas9 and guide RNA was injected into mice following anesthesia and the application of Scopisol to prevent reflux. Subtenon’s injections were administered at two locations around each eye, spaced 180 degrees apart (while avoiding blood vessels) as previous reported (Supplementary Figure S1 ) (Ikeda et al 2022 ; Zhao et al 2018 ). A 33 G needle was used for the injections, and the eyes were covered with 0.2% polyacrylic acid for the 3 days following the injection.…”

Section: Methodsmentioning

confidence: 99%

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Scleral remodeling during myopia development in mice eyes: a potential role of thrombospondin-1

Chen,

Ikeda,

Yang

et al. 2024

Mol Med

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Background Scleral extracellular matrix (ECM) remodeling plays a crucial role in the development of myopia, particularly in ocular axial elongation. Thrombospondin-1 (THBS1), also known as TSP-1, is a significant cellular protein involved in matrix remodeling in various tissues. However, the specific role of THBS1 in myopia development remains unclear. Method We employed the HumanNet database to predict genes related to myopic sclera remodeling, followed by screening and visualization of the predicted genes using bioinformatics tools. To investigate the potential target gene Thbs1, we utilized lens-induced myopia models in male C57BL/6J mice and performed Western blot analysis to detect the expression level of scleral THBS1 during myopia development. Additionally, we evaluated the effects of scleral THBS1 knockdown on myopia development through AAV sub-Tenon’s injection. The refractive status and axial length were measured using a refractometer and SD-OCT system. Results During lens-induced myopia, THBS1 protein expression in the sclera was downregulated, particularly in the early stages of myopia induction. Moreover, the mice in the THBS1 knockdown group exhibited alterations in myopia development in both refraction and axial length changed compared to the control group. Western blotting analysis confirmed the effectiveness of AAV-mediated knockdown, demonstrating a decrease in COLA1 expression and an increase in MMP9 levels in the sclera. Conclusion Our findings indicate that sclera THBS1 levels decreased during myopia development and subsequent THBS1 knockdown showed a decrease in scleral COLA1 expression. Taken together, these results suggest that THBS1 plays a role in maintaining the homeostasis of scleral extracellular matrix, and the reduction of THBS1 may promote the remodeling process and then affect ocular axial elongation during myopia progression.

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Sonodynamic Therapy of NRP2 Monoclonal Antibody‐Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy‐Dependent Ferroptosis

Zhao,

Wu,

Liang

et al. 2023

Advanced Science

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The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron‐based metal organic framework (Fe‐MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer‐specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non‐targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule‐associated protein 1A/1B‐light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy‐dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.

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Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

Cited by 20 publications

References 49 publications

Establishment of a novel ER-stress induced myopia model in mice

Establishment of a novel ER-stress induced myopia model in mice

Scleral remodeling during myopia development in mice eyes: a potential role of thrombospondin-1

Sonodynamic Therapy of NRP2 Monoclonal Antibody‐Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy‐Dependent Ferroptosis

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