Dataset Information

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

ABSTRACT: Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

SUBMITTER: Ikeda SI

PROVIDER: S-EPMC9550863 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Ikeda Shin-Ichi SI Kurihara Toshihide T Jiang Xiaoyan X Miwa Yukihiro Y Lee Deokho D Serizawa Naho N Jeong Heonuk H Mori Kiwako K Katada Yusaku Y Kunimi Hiromitsu H Ozawa Nobuhiro N Shoda Chiho C Ibuki Mari M Negishi Kazuno K Torii Hidemasa H Tsubota Kazuo K

Nature communications 20221010 1

Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for E ...[more]

PMID: 36216837

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Project description:AimTo explore the photopic pupil size behavior in myopic children undergoing overnight orthokeratology (ortho-k) over 1-year period and its effects on the axial elongation.MethodsA total of 202 Chinese myopic children were enrolled in this prospective clinical trial. Ninety-five subjects in ortho-k group and eighty-eight subjects in spectacle group completed the 1-year study. Axial length (AL) was measured before enrollment and every 6mo after the start of ortho-k. The photopic pupil diameter (PPD) was determined using the Pentacam AXL and measured in an examination room with lighting of 300-310 Lx. Stepwise multiple linear regression analysis was used to identify variables contribution to axial elongation.ResultsCompared with spectacle group, the average 1-year axial elongation was significantly slower in the ortho-k group (0.25±0.27 vs 0.44±0.23 mm, P<0.0001). In ortho-k group, PPDs significantly decreased from 4.21±0.62 mm to 3.94±0.53 mm after 1mo of lens wear (P=0.001, Bonferroni correction) and the change lasts for 3-month visit. No significantly change during the other follow-up visits was found (P>0.05, Bonferroni correction). The 4.81 mm PPD may be a possible cutoff point in the ortho-k group. Subjects with PPD below or equal to 4.81 mm tended to have smaller axial elongation compared to subjects with PPD above 4.81 mm after 1-year period (t=-3.09, P=0.003). In ortho-k group, univariate analyses indicated that those with older age, greater degree of myopia, longer AL, smaller baseline PPD (PPDbaseline) experienced a smaller change in AL. In multivariate analyses, older age, greater AL and smaller PPDbaseline were associated with smaller increases in AL. In spectacle group, PPD tended to be stable (P>0.05, Bonferroni correction) and did not affect axial growth.ConclusionPPDs experience significantly decreases at 1-month and 3-month ortho-k treatment. Children with smaller PPD tend to experience slower axial elongation and may benefit more from ortho-k.

Dataset Information

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

Publications

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

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