Publications by authors named "Xiangtian Zhou"

132 Publications

Dietary ω-3 polyunsaturated fatty acids are protective for myopia.

Proc Natl Acad Sci U S A 2021 Oct;118(43)

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China;

Myopia is a leading cause of visual impairment and blindness worldwide. However, a safe and accessible approach for myopia control and prevention is currently unavailable. Here, we investigated the therapeutic effect of dietary supplements of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on myopia progression in animal models and on decreases in choroidal blood perfusion (ChBP) caused by near work, a risk factor for myopia in young adults. We demonstrated that daily gavage of ω-3 PUFAs (300 mg docosahexaenoic acid [DHA] plus 60 mg eicosapentaenoic acid [EPA]) significantly attenuated the development of form deprivation myopia in guinea pigs and mice, as well as of lens-induced myopia in guinea pigs. Peribulbar injections of DHA also inhibited myopia progression in form-deprived guinea pigs. The suppression of myopia in guinea pigs was accompanied by inhibition of the "ChBP reduction-scleral hypoxia cascade." Additionally, treatment with DHA or EPA antagonized hypoxia-induced myofibroblast transdifferentiation in cultured human scleral fibroblasts. In human subjects, oral administration of ω-3 PUFAs partially alleviated the near-work-induced decreases in ChBP. Therefore, evidence from these animal and human studies suggests ω-3 PUFAs are potential and readily available candidates for myopia control.
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http://dx.doi.org/10.1073/pnas.2104689118DOI Listing
October 2021

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia.

Genomics Proteomics Bioinformatics 2021 Oct 5. Epub 2021 Oct 5.

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; Collaborative Innovation Center for Genetics and Development, Shanghai 200438, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Postzygotic mutations are acquired in normal tissues throughout an individual's lifetime and hold clues for identifying mutagenic factors. We investigated postzygotic mutation spectra in healthy individuals using optimized ultra-deep exome sequencing of time-series samples from the same volunteer and samples from different individuals. In blood, sperm, and muscle cells, we resolved three common types of mutational signatures. Signatures A and B represent clock-like mutational processes, and polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles. Notably, signature C, characterized by C>T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type are likely to occur early during embryonic development, supported by their relatively high allelic frequencies, presence in multiple tissues, and decrease in occurrence with age. Almost none of the public datasets for tumors feature this signature, except for 19.6% of samples of clear-cell renal-cell carcinoma with increased activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Moreover, the accumulation of signature C in the mutational profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α. Thus, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites; and individuals' genetic background may also influence their postzygotic mutation profiles.
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http://dx.doi.org/10.1016/j.gpb.2021.09.005DOI Listing
October 2021

Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design.

J Genet Genomics 2021 Sep 11. Epub 2021 Sep 11.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510000, China. Electronic address:

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies (GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent (SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou (631 < -6D and 574 > 0D) and Wenzhou (593 < -6D and 54 > -1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci which show genome-wide significant associations with SE, including 1q25.2 FAM163A, 10p11.22 NRP1/PRAD3, and 10p11.21 ANKRD30A/MTRNR2L7, together explaining 3.34% of SE variance. 10p11.21 was successfully replicated. The allele frequencies of all three loci show significant differences between major continental groups (P < 0.001). The SE reducing (more myopic) allele of rs10913877 (1q25.2 FAM163A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS = 0.60, EUR = 0.20, AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5 and ARPP19. These results provide new insights into myopia pathogenesis, and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.
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http://dx.doi.org/10.1016/j.jgg.2021.08.011DOI Listing
September 2021

Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression.

Exp Eye Res 2021 Nov 8;212:108758. Epub 2021 Sep 8.

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China; Research Unit of Myopia Basic Research and Clinical Prevention and Control, Chinese Academy of Medical Sciences (2019RU025), Wenzhou, Zhejiang, China. Electronic address:

Myopia is the most common cause of a visual refractive error worldwide. Cyclic adenosine monophosphate (cAMP)-linked signaling pathways contribute to the regulation of myopia development, and increases in cAMP accumulation promote myopia progression. To pinpoint the underlying mechanisms by which cAMP modulates myopia progression, we performed scleral transcriptome sequencing analysis in form-deprived mice, a well-established model of myopia development. Form deprivation significantly inhibited the expression levels of genes in the cAMP catabolic pathway. Quantitative real-time polymerase chain reaction analysis validated that the gene expression level of phosphodiesterase 4B (PDE4B), a cAMP hydrolase, was downregulated in form-deprived mouse eyes. Under visually unobstructed conditions, loss of PDE4B function in Pde4b-knockout mice increased the myopic shift in refraction, -3.661 ± 1.071 diopters, more than that in the Pde4b-wildtype littermates (P < 0.05). This suggests that downregulation and inhibition of PDE4B gives rise to myopia. In guinea pigs, subconjunctival injection of rolipram, a selective inhibitor of PDE4, led to myopia in normal eyes, and it also enhanced form-deprivation myopia (FDM). Subconjunctival injection of dibutyryl-cyclic adenosine monophosphate, a cAMP analog, induced only a myopic shift in the normal visually unobstructed eyes, but it did not enhance FDM. As myopia developed, axial elongation occurred during scleral remodeling that was correlated with changes in collagen fibril thickness and distribution. The median collagen fibril diameter in the FDM + rolipram group, 55.09 ± 1.83 nm, was thinner than in the FDM + vehicle group, 59.33 ± 2.06 nm (P = 0.011). Thus, inhibition of PDE4 activity with rolipram thinned the collagen fibril diameter relative to the vehicle treatment in form-deprived eyes. Rolipram also inhibited increases in collagen synthesis induced by TGF-β2 in cultured human scleral fibroblasts. The current results further support a role for PDE enzymes such as PDE4B in the regulation of normal refractive development and myopia because either loss or inhibition of PDE4B function increased myopia and FDM development through declines in the scleral collagen fibril diameter.
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http://dx.doi.org/10.1016/j.exer.2021.108758DOI Listing
November 2021

Differences in Retinal and Choroidal Vasculature and Perfusion Related to Axial Length in Pediatric Anisomyopes.

Invest Ophthalmol Vis Sci 2021 07;62(9):40

Eye Hospital and School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: The purpose of this study was to evaluate the interocular differences in choroidal vasculature, choriocapillaris perfusion, and retinal microvascular network, and to explore their associations with interocular asymmetry in axial lengths (ALs) in children with anisomyopia.

Methods: Refractive error, AL, and other biometric parameters were measured in 70 children with anisomyopia. Using optical coherence tomography (OCT) and OCT-angiography, we measured the submacular choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), choriocapillaris flow deficit (CcFD), retinal vessel density (VD), and foveal avascular zone (FAZ) area.

Results: The mean interocular differences in spherical equivalent refraction and AL were -2.26 ± 0.94 diopters and 0.95 ± 0.46 mm, respectively. Submacular ChT, TCA, LA, SA, and CVI were all significantly lower in the more myopic (longer AL) eyes than in the less myopic (shorter AL) fellow eyes. In eyes with longer ALs, both the CcFD and FAZ areas were significantly greater, whereas the superficial and deep retinal VDs were significantly less. After adjusting for corneal power and intraocular pressure, interocular differences in LA (β = -0.774), SA (β = -0.991), and CcFD (β = 0.040) were significantly associated with interocular asymmetry in AL (all P < 0.05).

Conclusions: In pediatric anisomyopes, eyes with longer ALs tended to have lower choroidal vascularity and choriocapillaris perfusion than the contralateral eyes with shorter ALs. Longitudinal investigations would be useful follow-ups to test for a causal role of choroidal circulation in human myopia.
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http://dx.doi.org/10.1167/iovs.62.9.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322721PMC
July 2021

Assocation Between Leber's Hereditary Optic Neuropathy and MT-ND1 3460G>A Mutation-Induced Alterations in Mitochondrial Function, Apoptosis, and Mitophagy.

Invest Ophthalmol Vis Sci 2021 07;62(9):38

Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: To investigate the molecular mechanism underlying the Leber's hereditary optic neuropathy (LHON)-linked MT-ND1 3460G>A mutation.

Methods: Cybrid cell models were generated by fusing mitochondrial DNA-less ρ0 cells with enucleated cells from a patient carrying the m.3460G>A mutation and a control subject. The impact of m.3460G>A mutations on oxidative phosphorylation was evaluated using Blue Native gel electrophoresis, and measurements of oxygen consumption were made with an extracellular flux analyzer. Assessment of reactive oxygen species (ROS) production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Assays for apoptosis and mitophagy were undertaken via immunofluorescence analysis.

Results: Nineteen Chinese Han pedigrees bearing the m.3460G>A mutation exhibited variable penetrance and expression of LHON. The m.3460G>A mutation altered the structure and function of MT-ND1, as evidenced by reduced MT-ND1 levels in mutant cybrids bearing the mutation. The instability of mutated MT-ND1 manifested as defects in the assembly and activity of complex I, respiratory deficiency, diminished mitochondrial adenosine triphosphate production, and decreased membrane potential, in addition to increased production of mitochondrial ROS in the mutant cybrids carrying the m.3460G>A mutation. The m.3460G>A mutation mediated apoptosis, as evidenced by the elevated release of cytochrome c into the cytosol and increasing levels of the apoptotic-associated proteins BAK, BAX, and PARP, as well as cleaved caspases 3, 7, and 9, in the mutant cybrids. The cybrids bearing the m.3460G>A mutation exhibited reduced levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PTEN-induced kinase 1/parkin-dependent mitophagy.

Conclusions: Our findings highlight the critical role of m.3460G>A mutation in the pathogenesis of LHON, manifested by mitochondrial dysfunction and alterations in apoptosis and mitophagy.
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http://dx.doi.org/10.1167/iovs.62.9.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322717PMC
July 2021

The Role of Retinal Connexins Cx36 and Horizontal Cell Coupling in Emmetropization in Guinea Pigs.

Invest Ophthalmol Vis Sci 2021 07;62(9):27

School of Optometry and Ophthalmology, and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: The purpose of this study was to determine whether retinal gap junctions (GJs) via connexin 36 (Cx36, mediating coupling of many retinal cell types) and horizontal cell (HC-HC) coupling, are involved in emmetropization.

Methods: Guinea pigs (3 weeks old) were monocularly form deprived (FD) or raised without FD (in normal visual [NV] environment) for 2 days or 4 weeks; alternatively, they wore a -4 D lens (hyperopic defocus [HD]) or 0 D lens for 2 days or 1 week. FD and NV eyes received daily subconjunctival injections of a nonspecific GJ-uncoupling agent, 18-β-Glycyrrhetinic Acid (18-β-GA). The amounts of total Cx36 and of phosphorylated Cx36 (P-Cx36; activated state that increases cell-cell coupling), in the inner and outer plexiform layers (IPLs and OPLs), were evaluated by quantitative immunofluorescence (IF), and HC-HC coupling was evaluated by cut-loading with neurobiotin.

Results: FD per se (excluding effect of light-attenuation) increased HC-HC coupling in OPL, whereas HD did not affect it. HD for 2 days or 1 week had no significant effect on retinal content of Cx36 or P-Cx36. FD for 4 weeks decreased the total amounts of Cx36 and P-Cx36, and the P-Cx36/Cx36 ratio, in the IPL. Subconjunctival 18-β-GA induced myopia in NV eyes and increased the myopic shifts in FD eyes, while reducing the amounts of Cx36 and P-Cx36 in both the IPL and OPL.

Conclusions: These results suggest that cell-cell coupling via GJs containing Cx36 (particularly those in the IPL) plays a role in emmetropization and form deprivation myopia (FDM) in mammals. Although both FD and 18-β-GA induced myopia, they had opposite effects on HC-HC coupling. These findings suggest that HC-HC coupling in the OPL might not play a significant role in emmetropization and myopia development.
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http://dx.doi.org/10.1167/iovs.62.9.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300059PMC
July 2021

Canonical Wnt Signaling Drives Myopia Development and Can Be Pharmacologically Modulated.

Invest Ophthalmol Vis Sci 2021 07;62(9):21

Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, Xiamen University, Xiamen, Fujian, China.

Purpose: The purpose of this study was to evaluate the role of the canonical Wnt signaling in the development of the myopia.

Methods: Plasma from adult patients with myopia, myopic animal models including the adenomatous polyposis coli (APC) gene mutation mouse model, and the form deprivation (FD) induced mouse model of myopia were used. Niclosamide, a canonical Wnt pathway inhibitor, was orally administrated in animal models. Plasma levels of DKK-1 were determined by using enzyme-linked immunosorbent assay. Refraction, vitreous chamber depth (VCD), axial length (AL), and other parameters, were measured at the end of the FD treatment. Canonical Wnt signaling changes were evaluated by Western blot analysis and immunostaining analysis.

Results: Plasma level of Wnt inhibitor DKK-1 was markedly decreased in patients with myopia. Meanwhile, the canonical Wnt pathway was progressively activated during myopia development in mice. Moreover, inhibition of canonical Wnt signaling by niclosamide in mouse models markedly reduced lens thickness (LT), VCD, and AL elongation, resulting in myopia inhibition.

Conclusions: Dysregulation of canonical Wnt signaling is a characteristic of myopia and targeting Wnt signaling pathways has potential as a therapeutic strategy for myopia.
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http://dx.doi.org/10.1167/iovs.62.9.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288060PMC
July 2021

Author Correction: A role of color vision in emmetropization in C57BL/6J mice.

Sci Rep 2021 Apr 14;11(1):8556. Epub 2021 Apr 14.

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325027, Zhejiang, China.

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http://dx.doi.org/10.1038/s41598-021-88185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046967PMC
April 2021

From Establishing a World-Renowned Eye Institute to Integrating Ophthalmology and Optometry in China: The Story of The Eye Hospital of Wenzhou Medical University.

Asia Pac J Ophthalmol (Phila) 2021 Mar-Apr 01;10(2):135-141

School of Ophthalmology and Optometry, Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Abstract: The Eye Hospital of Wenzhou Medical University (the Eye Hospital) has found its ways to thrive within the contexts of China to become one of the world-leading institutes in providing ophthalmology and optometry training, education, research, and clinical care at the international standards within 2 decades. It is also the only eye institute in China that possesses 3 national-level research centers (National Clinical Research Center for Ocular Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, and National Engineering Technology Research Center for Ophthalmology and Optometry). The hospital is instrumental to the unique medical program in which medical graduates could be both medical doctors and optometrists. Over 10% of the eye doctors in China were trained by the hospital. The SCI-indexed journal Eye and Vision, which is the top eye journal from China, was established by the Eye Hospital in 2015. Its recent endeavor entitled "Eye Valley" provides a one-stop platform for innovation and technology incubation, basic research to clinical trial, from US Food & Drug Administration (FDA) registration to drug production, etc. This article reviews the history of development of the Eye Hospital and elaborates its spirit of "making the impossible possible", which has guided it all the way through from an unknown regional to a renowned top-tier hospital with national and global recognition as a first-class institution.
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http://dx.doi.org/10.1097/APO.0000000000000389DOI Listing
October 2021

EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development.

Invest Ophthalmol Vis Sci 2021 02;62(2):31

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: We used a mouse model to explore the role of the endoplasmic reticulum membrane protein complex subunit 3 (EMC3) in mammalian retinal development.

Methods: The transcription pattern of Emc3 in C57BL/6 mice was analyzed by in situ hybridization. To explore the effects of EMC3 absence on retinal development, the Cre-loxP system was used to generate retina-specific Emc3 in knockout mice (Emc3flox/flox, Six3-cre+; CKO). Morphological changes in the retina of E13.5, E17.5, P0.5, and P7 mice were observed via hematoxylin and eosin staining. Immunofluorescence staining was used to assess protein distribution and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to assess apoptosis changes. Proteins were identified and quantified by Western blotting and proteomic analysis. Electroretinogram (ERG), fundus color photography, and optical coherence tomography were performed on 5-week-old mice to evaluate retinal function and structure.

Results: The Emc3 mRNA was widely distributed in the whole retina during development. Loss of retinal EMC3 led to retinal rosette degeneration with mislocalization of cell junction molecules (β-catenin, N-cadherin, and zonula occludens-1) and polarity molecules (Par3 and PKCζ). Endoplasmic reticulum stress and TUNEL apoptosis signals were present in retinal rosette-forming cells. Although the absence of EMC3 promoted the production of photoreceptor cells, 5-week-old mice lost all visual function and had severe retinal morphological degeneration.

Conclusions: EMC3 regulates retinal structure by maintaining the polarity of retinal progenitor cells and regulating retinal cell apoptosis.
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http://dx.doi.org/10.1167/iovs.62.2.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900856PMC
February 2021

Choroidal blood perfusion as a potential "rapid predictive index" for myopia development and progression.

Eye Vis (Lond) 2021 Jan 4;8(1). Epub 2021 Jan 4.

Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Myopia is the leading cause of visual impairment worldwide. The lack of a "rapid predictive index" for myopia development and progression hinders the clinic management and prevention of myopia. This article reviews the studies describing changes that occur in the choroid during myopia development and proposes that it is possible to detect myopia development at an earlier stage than is currently possible in a clinical setting using choroidal blood perfusion as a "rapid predictive index" of myopia.
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http://dx.doi.org/10.1186/s40662-020-00224-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780679PMC
January 2021

Assessment of Choroidal Vascularity and Choriocapillaris Blood Perfusion in Anisomyopic Adults by SS-OCT/OCTA.

Invest Ophthalmol Vis Sci 2021 01;62(1)

Eye Hospital and School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: To explore the association of choroidal vascularity and choriocapillaris blood perfusion with myopic severity in anisomyopes.

Methods: Refractive error, axial length (AL), and other biometric parameters were measured in 34 anisomyopic young adults. Macular choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI), were determined from swept-source optical coherence tomography (SS-OCT) vertical and horizontal B-scans. The percentage of choriocapillaris flow voids (FV%) was obtained from en face SS-OCT-angiography.

Results: The spherical equivalent refraction (SER) was -3.35 ± 1.25 diopters in the more myopic eyes and -1.25 ± 1.17 diopters in the less myopic eyes (P < 0.001). The interocular difference in SER was highly correlated with that in AL (P < 0.001). The macular ChT, TCA, LA, and SA were smaller in the more myopic eyes than in the less myopic eyes in both vertical and horizontal scans (all P < 0.001). Importantly, the CVIs in vertical and horizontal scans were smaller and the FV% was greater in the more myopic eyes (P < 0.05). In vertical scans, the interocular difference in CVIs was correlated with that in the SER, AL, and ChT (all P < 0.05). The interocular difference in FV% was correlated with that in SER, AL, and vertical and horizontal ChTs (all P < 0.05).

Conclusions: Choroidal vascularity and choriocapillaris blood perfusion were lower in the more myopic eyes of anisomyopic adults. These changes were correlated with the severity of myopia and choroidal thinning, indicating that choroidal blood flow is disturbed in human myopia.
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http://dx.doi.org/10.1167/iovs.62.1.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797932PMC
January 2021

Myopia.

Nat Rev Dis Primers 2020 12 17;6(1):99. Epub 2020 Dec 17.

Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.

Myopia, also known as short-sightedness or near-sightedness, is a very common condition that typically starts in childhood. Severe forms of myopia (pathologic myopia) are associated with a risk of other associated ophthalmic problems. This disorder affects all populations and is reaching epidemic proportions in East Asia, although there are differences in prevalence between countries. Myopia is caused by both environmental and genetic risk factors. A range of myopia management and control strategies are available that can treat this condition, but it is clear that understanding the factors involved in delaying myopia onset and slowing its progression will be key to reducing the rapid rise in its global prevalence. To achieve this goal, improved data collection using wearable technology, in combination with collection and assessment of data on demographic, genetic and environmental risk factors and with artificial intelligence are needed. Improved public health strategies focusing on early detection or prevention combined with additional effective therapeutic interventions to limit myopia progression are also needed.
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http://dx.doi.org/10.1038/s41572-020-00231-4DOI Listing
December 2020

Dysfunction of VIPR2 leads to myopia in humans and mice.

J Med Genet 2020 Dec 14. Epub 2020 Dec 14.

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China

Background: Myopia is the leading cause of refractive errors. As its pathogenesis is poorly understood, we determined if the retinal VIP-VIPR2 signalling pathway axis has a role in controlling signalling output that affects myopia development in mice.

Methods: Association analysis meta-study, single-cell transcriptome, bulk RNA sequencing, pharmacological manipulation and VIPR2 gene knockout studies were used to clarify if changes in the VIP-VIPR2 signalling pathway affect refractive development in mice.

Results: The SNP rs6979985 of the gene was associated with high myopia in a Chinese Han cohort (randomceffect model: p=0.013). After either 1 or 2 days' form deprivation (FD) retinal mRNA expression was downregulated. Retinal single-cell transcriptome sequencing showed that VIPR2 expressed mainly by bipolar cells. Furthermore, the cAMP signalling pathway axis was inhibited in some clusters after 2 days of FD. The selective VIPR2 antagonist PG99-465 induced relative myopia, whereas the selective VIPR2 agonist Ro25-1553 inhibited this response. In knockout (-KO) mice, refraction was significantly shifted towards myopia (p<0.05). The amplitudes of the bipolar cell derived b-waves in 7-week-old -KO mice were significantly larger than those in their WT littermates (p<0.05).

Conclusions: Loss of VIPR2 function likely compromises bipolar cell function based on presumed changes in signal transduction due to altered signature electrical wave activity output in these mice. As these effects correspond with increases in form deprivation myopia (FDM), the VIP-VIPR2 signalling pathway axis is a viable novel target to control the development of this condition.
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http://dx.doi.org/10.1136/jmedgenet-2020-107220DOI Listing
December 2020

Increased Choroidal Blood Perfusion Can Inhibit Form Deprivation Myopia in Guinea Pigs.

Invest Ophthalmol Vis Sci 2020 11;61(13):25

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: In guinea pigs, choroidal thickness (ChT) and choroidal blood perfusion (ChBP) simultaneously decrease in experimental myopia, and both increase during recovery. However, the causal relationship between ChBP and myopia requires further investigation. In this study, we examined the changes of ChBP with three different antimyopia treatments. We also actively increased ChBP to examine the direct effect on myopia development in guinea pigs.

Methods: Experiment 1: Guinea pigs wore occluders on the right eye for two weeks to induce form-deprivation myopia (FDM). Simultaneously they received daily antimyopia treatments: peribulbar injections of atropine or apomorphine or exposure to intense light. Experiment 2: The vasodilator prazosin was injected daily into the form-deprivation eyes to increase ChBP during the two-week induction of FDM. Other FDM animals received appropriate control treatments. Changes in refraction, axial length, ChBP, ChT, and hypoxia-labeled pimonidazole adducts in the sclera were measured.

Results: The antimyopia treatments atropine, apomorphine, and intense light all significantly inhibited myopia development and the decrease in ChBP. The treatments also reduced scleral hypoxia, as indicated by the decrease in hypoxic signals. Furthermore, actively increasing ChBP with prazosin inhibited the progression of myopia, as well as the increase in axial length and scleral hypoxia.

Conclusions: Our data strongly indicate that increased ChBP attenuates scleral hypoxia, and thereby inhibits the development of myopia. Thus ChBP may be a promising target for myopia retardation. As such, it can serve as an immediate predictor of myopia development as well as a long-term marker of it.
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http://dx.doi.org/10.1167/iovs.61.13.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683853PMC
November 2020

PPARγ modulates refractive development and form deprivation myopia in Guinea pigs.

Exp Eye Res 2021 01 2;202:108332. Epub 2020 Nov 2.

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; State Key Laboratory of Optometry, Ophthalmology, and Vision Science, Wenzhou, Zhejiang, China; Research Unit of Myopia Basic Research and Clinical Prevention and Control, Chinese Academy of Medical Sciences (2019RU025), China. Electronic address:

Form deprivation myopia (FDM) is characterized by loss of choroidal thickness (ChT), reduced choroidal blood perfusion (ChBP), and consequently scleral hypoxia. In some tissues, changes in levels of peroxisome proliferator-activated receptor γ (PPARγ) expression modulate hypoxia-induced pathological responses. We determined if PPARγ modulates FDM through changes in ChT, ChBP, scleral hypoxia-inducible transcription factor (HIF-1α) that in turn regulate scleral collagen type 1 (COL1) expression levels in guinea pigs. Myopia was induced by occluding one eye, while the fellow eye served as control. They received daily peribulbar injections of either the PPARγ antagonist GW9662, or the GW1929 agonist, with or without ocular occlusion for 4 weeks. Ocular refraction and biometric parameters were estimated at baseline, 2 and 4 weeks post-treatment. ChT and ChBP were measured at the 2- and 4-week time points. Western blot analysis determined the expression levels of scleral HIF-1α and COL1. GW9662 induced a myopic shift in unoccluded eyes. Conversely, GW1929 inhibited FDM progression without affecting the refraction in unoccluded eyes. GW9662 reduced both ChT and ChBP in unoccluded eyes, while GW1929 inhibited their declines in occluded eyes. Scleral HIF-1α expression rose in GW9662-treated unoccluded eyes whereas GW1929 reduced HIF-1α upregulation in occluded eyes. GW9662 downregulated scleral COL1 expression in unoccluded eyes, while GW1929 reduced their decreases in occluded eyes. Therefore, PPARγ modulates collagen expression levels and FDM through an inverse relationship between changes in PPARγ and HIF-1α expression levels.
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http://dx.doi.org/10.1016/j.exer.2020.108332DOI Listing
January 2021

LIM-Homeodomain Transcription Factor LHX4 Is Required for the Differentiation of Retinal Rod Bipolar Cells and OFF-Cone Bipolar Subtypes.

Cell Rep 2020 09;32(11):108144

Department of Neuroscience & Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY 14642, USA. Electronic address:

Retinal bipolar cells (BCs) connect with photoreceptors and relay visual information to retinal ganglion cells (RGCs). Retina-specific deletion of Lhx4 in mice results in a visual defect resembling human congenital stationary night blindness. This visual dysfunction results from the absence of rod bipolar cells (RBCs) and the loss of selective rod-connecting cone bipolar cell (CBC) subtypes and AII amacrine cells (ACs). Inactivation of Lhx4 causes the apoptosis of BCs and cell fate switch from some BCs to ACs, whereas Lhx4 overexpression promotes BC genesis. Moreover, Lhx4 positively regulates Lhx3 expression to drive the fate choice of type 2 BCs over the GABAergic ACs. Lhx4 inactivation ablates Bhlhe23 expression, whereas overexpression of Bhlhe23 partially rescues RBC development in the absence of Lhx4. Thus, by acting upstream of Bhlhe23, Prdm8, Fezf2, Lhx3, and other BC genes, Lhx4, together with Isl1, could play essential roles in regulating the subtype-specific development of RBCs and CBCs.
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http://dx.doi.org/10.1016/j.celrep.2020.108144DOI Listing
September 2020

A role of color vision in emmetropization in C57BL/6J mice.

Sci Rep 2020 09 10;10(1):14895. Epub 2020 Sep 10.

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325027, Zhejiang, China.

Spectral composition affects emmetropization in both humans and animal models. Because color vision interacts the effects of chromatic defocus, we developed a method to bypass the effects of longitudinal chromatic aberration by placing a spectral filter behind the optics of the eye, using genetic tools. Newborn C57BL/6J (B6) mice were reared in quasi-monochromatic red (410-510 nm) or blue (585-660 nm) light beginning before eye-opening. Refractive states and ocular dimensions were compared at 4, 6, 8, and 10 weeks with mice reared in normal white light. Cre recombinase-dependent Ai9 reporter mice were crossed with Chx10-Cre to obtain Chx10-Cre;Ai9 mice, expressing red fluorescent protein in retinal Cre-positive cells. Ai9 offsprings, with and without Cre, were reared under a normal visual environment. Refraction and axial components were measured as described above. Expression levels of M and S opsin were quantified by western blotting at 10 weeks. Compared with those reared in white light, B6 mice reared in red light developed relative hyperopia, principally characterized by flattening of corneal curvature. Emmetropization was not affected by blue light, possibly because the reduction in vitreous chamber depth compensated for the increase in corneal curvature. Compared with Cre-negative littermates, the refraction and axial dimensions of Chx10-Cre;Ai9 mice were not significantly different at the follow-up timepoints. M opsin levels were higher in Chx10-Cre;Ai9 mice at 10 weeks while S opsin levels were not different. Red light induced a hyperopic shift in mouse refractive development. Emmetropization was not impacted in mice with perturbed color vision caused by intrinsic red-fluorescent protein, suggesting that color vision may not be necessary in mouse emmetropization when other mechanisms are present.
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http://dx.doi.org/10.1038/s41598-020-71806-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483713PMC
September 2020

Crosstalk between EP2 and PPARα Modulates Hypoxic Signaling and Myopia Development in Guinea Pigs.

Invest Ophthalmol Vis Sci 2020 07;61(8):44

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Purpose: Cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor alpha (PPARα) levels mediate extracellular matrix (ECM) changes by altering the levels of hypoxia-inducible factor 1-alpha (HIF-1α) in various tissues. We aimed to determine, in the sclera of guinea pigs, whether a prostanoid receptor (EP2)-linked cAMP modulation affects PPARα and HIF-1α signaling during myopia.

Methods: Three-week-old guinea pigs (n = 20 in each group), were monocularly injected with either an EP2 agonist (butaprost 1 µmol/L/10 µmol/L), an antagonist (AH6809 10 µmol/L/30 µmol/L) or a vehicle solution for two weeks during normal ocular growth. Separate sets of animals received these injections and underwent form deprivation (FD) simultaneously. Refraction and axial length (AL) were measured at two weeks, followed by scleral tissue isolation for quantitative PCR (qPCR) analysis (n = 10) and cAMP detection (n = 10) using a radioimmunoassay.

Results: Butaprost induced myopia development during normal ocular growth, with proportional increases in AL and cAMP levels. FD did not augment the magnitude of myopia or cAMP elevations in these agonist-injected eyes. AH6809 suppressed cAMP increases and myopia progression during FD, but had no effect in a normal visual environment. Of the diverse set of 27 genes related to cAMP, PPARα and HIF-1α signaling and ECM remodeling, butaprost differentially regulated 15 of them during myopia development. AH6809 injections during FD negated such differential gene expressions.

Conclusion: EP2 agonism increased cAMP and HIF-1α signaling subsequent to declines in PPARα and RXR mRNA levels, which in turn decreased scleral fibrosis and promoted myopia. EP2 antagonism instead inhibited each of these responses. Our data suggest that EP2 suppression may sustain scleral ECM structure and inhibit myopia development.
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http://dx.doi.org/10.1167/iovs.61.8.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425689PMC
July 2020

Scleral HIF-1α is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis.

EBioMedicine 2020 Jul 8;57:102878. Epub 2020 Jul 8.

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China. Electronic address:

Background: Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression.

Methods: Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro.

Results: All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia.

Interpretation: Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors.

Funding: National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.
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http://dx.doi.org/10.1016/j.ebiom.2020.102878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348000PMC
July 2020

The Role of the Dopamine D2 Receptor in Form-Deprivation Myopia in Mice: Studies With Full and Partial D2 Receptor Agonists and Knockouts.

Invest Ophthalmol Vis Sci 2020 06;61(6):47

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Purpose: The purpose of this study was to explore the role and mechanism of D2 receptor (D2R) involvement in myopia development and the effects of the full D2R agonist quinpirole and partial D2R agonist aripiprazole on postnatal refractive development and form-deprivation myopia (FDM).

Methods: C57BL/6 ("B6") mice, raised either in a visually normal or unilateral form-deprivation environment, were divided into three subgroups, including an intraperitoneally injected (IP) vehicle group and two quinpirole (1 and 10 µg/g body weight) treatment groups. The effects of quinpirole on FDM were further verified in D2R-knockout (KO) mice and corresponding wild-type littermates. Then, the modulation of normal vision development and FDM by aripiprazole (1 and 10 µg/g body weight, IP) was assessed in C57BL/6 mice. All biometric parameters were measured before and after treatments, and retinal cyclic adenosine phosphate (cAMP) and phosphorylated ERK (pERK) levels were analyzed to assess D2R-mediated signal transduction.

Results: Neither quinpirole nor aripiprazole affected normal refractive development. FDM development was inhibited by quinpirole at low dose but enhanced at high dose, and these bidirectional effects were validated by D2R-specificity. FDM development was attenuated by the partial D2R agonist aripiprazole, at high dose but not at low dose. Quinpirole caused a dose-dependent reduction in cAMP levels, but had no effect on pERK. Aripiprazole reduced cAMP levels at both doses, but caused a dose-dependent increase of pERK in the form-deprived eyes.

Conclusions: Reduction of D2R-mediated signaling contributes to myopia development, which can be selectively attenuated by partial D2R agonists that activate D2Rs under the low dopamine levels that occur with FDM.
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http://dx.doi.org/10.1167/iovs.61.6.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415310PMC
June 2020

Up-Regulation of Matrix Metalloproteinase-2 by Scleral Monocyte-Derived Macrophages Contributes to Myopia Development.

Am J Pathol 2020 09 16;190(9):1888-1908. Epub 2020 Jun 16.

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, China. Electronic address:

Myopia is a leading cause of visual impairment worldwide. This sight-compromising condition is associated with scleral thinning, extracellular matrix remodeling, and inappropriate optical axial length elongation. Although macrophages are present in the sclera, their involvement in this condition is unknown. By using a form-deprivation myopia (FDM) mouse model, we found that both the scleral macrophage density and their matrix metalloproteinase-2 (MMP-2) expression levels increased in myopic eyes. Partial scleral macrophage depletion by clodronate shifted the refraction toward hyperopia in both the form-deprived and the untreated fellow eyes compared with their respective counterparts in the vehicle-injected control mice. However, this procedure did not alter susceptibility to FDM. FDM development was 59% less in the macrophage-specific Mmp2 deletion (LysMMmp-2) mice than in their Cre-negative littermates (Mmp2 mice). Moreover, the expression of scleral C-C motif chemokine ligand-2 (CCL2), which is a potent monocyte chemoattractant recruiting monocytes to tissue sites, was increased during myopia progression. However, the increase in the density of scleral macrophages and myopia development were suppressed in fibroblast-specific Ccl2 deletion mice. These declines suggested that the increase in scleral macrophage density in myopic eyes stems from the up-regulation of scleral Ccl2 expression in fibroblasts, which, in turn, promotes monocytes recruitment. In summary, scleral monocyte-derived macrophages contribute to myopia development through enhancing MMP-2 expression in mice.
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http://dx.doi.org/10.1016/j.ajpath.2020.06.002DOI Listing
September 2020

Increased Connexin36 Phosphorylation in AII Amacrine Cell Coupling of the Mouse Myopic Retina.

Front Cell Neurosci 2020 1;14:124. Epub 2020 Jun 1.

Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Kowloon, Hong Kong.

Myopia is a substantial public health problem worldwide. In the myopic retina, distant images are focused in front of the photoreceptors. The cells and mechanisms for retinal signaling that account either for emmetropization (i.e., normal refraction) or for refractive errors have remained elusive. Gap junctions play a key component in enhancement of signal transmission in visual pathways. AII amacrine cells (ACs), coupled by connexin36, segregate signals into ON and OFF pathways. Coupling between AII ACs is actively modulated through phosphorylation at serine 293 via dopamine in the mouse retina. In this study, form deprivation mouse myopia models were used to evaluate the expression patterns of connexin36-positive plaques (structural assay) and the state of connexin36 phosphorylation (functional assay) in AII ACs, which was green fluorescent protein-expressing in the Fam81a mouse line. Single-cell RNA sequencing showed dopaminergic synapse and gap junction pathways of AII ACs were downregulated in the myopic retina, although Gjd2 mRNA expression remained the same. Compared with the normal refractive eye, phosphorylation of connexin36 was increased in the myopic retina, but expression of connexin36 remained unchanged. This increased phosphorylation of Cx36 could indicate increased functional gap junction coupling of AII ACs in the myopic retina, a possible adaptation to adjust to the altered noisy signaling status.
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http://dx.doi.org/10.3389/fncel.2020.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278884PMC
June 2020

PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy.

J Clin Invest 2020 09;130(9):4935-4946

Division of Medical Genetics and Genomics, Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole-exome sequencing, we identified the X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited defective assembly, stability, and function of ATP synthase, verified by PRICKLE3-knockdown cells. Coimmunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunction than those carrying only a single mutation. This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3-deficient mice exhibited pronounced ATPase deficiencies. Prickle3-knockout mice recapitulated LHON phenotypes with retinal deficiencies, including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutations and X-linked nuclear modifiers.
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http://dx.doi.org/10.1172/JCI134965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456240PMC
September 2020

Optic nerve crush modulates refractive development of the C57BL/6 mouse by changing multiple ocular dimensions.

Brain Res 2020 01 28;1726:146537. Epub 2019 Oct 28.

State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology and Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address:

Higher visual centers could modulate visually-guided ocular growth, in addition to local mechanisms intrinsic to the eye. There is evidence that such central modulations could be species (even subspecies)-dependent. While the mouse has recently become an important experimental animal in myopia studies, it remains unclear whether and how visual centers modulate refractive development in mice, an issue that was examined in the present study. We found that optic nerve crush (ONC), performed at P18, could modify normal refractive development in the C57BL/6 mouse raised in normal visual environment. Unexpectedly, sham surgery caused a steeper cornea, leading to a modest myopic refractive shift, but did not induce significant changes in ocular axis length. ONC caused corneal flattening and re-calibrated the refractive set-point in a bidirectional manner, causing significant myopic (<-3 D, 54.5%) or hyperopic (>+3 D, 18.2%) shifts in refractive error in most (totally 72.7%) animals, both due to changes in ocular axial length. ONC did not change the density of dopaminergic amacrine cells, but increased retinal levels of dopamine and DOPAC. We conclude that higher visual centers are likely to play a role in fine-tuning of ocular growth, thus modifying refractive development in the C57BL/6 mouse. The changes in refractive error induced by ONC are accounted for by alternations in multiple ocular dimensions, including corneal curvature and axial length.
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http://dx.doi.org/10.1016/j.brainres.2019.146537DOI Listing
January 2020

Changes in Choroidal Thickness and Choroidal Blood Perfusion in Guinea Pig Myopia.

Invest Ophthalmol Vis Sci 2019 07;60(8):3074-3083

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: The purpose of this study was to study changes in choroidal thickness (ChT) and choroidal blood perfusion (ChBP), and the correlation between them, in guinea pig myopia.

Methods: The reliability of optical coherence tomography angiography (OCTA) for measuring ChT and ChBP was verified in guinea pigs, after cervical dislocation (n = 7) or temporal ciliary artery transection (n = 6). Changes in refraction, axial length, ChT, and ChBP were measured during spontaneous myopia (n = 9), monocular form-deprivation myopia (FDM, n = 13), or lens-induced myopia (LIM, n = 14), and after 4 days of recovery from FDM and LIM.

Results: The abolition (by cervical dislocation) or reduction (by temporal ciliary artery transection) of ChBP, and of the associated changes in ChT, were verified by OCTA, thus validating the method of measurement. In the spontaneous myopia group, ChT and ChBP were reduced by 25.2% and 31.9%, respectively. In FDM eyes, mean ± SD ChT and ChBP decreased significantly compared with the untreated fellow eyes (ChT fellow: 76.13 ± 9.34 μm versus 64.76 ± 11.15 μm for FDM; ChBP fellow: 37.87 ± 6.37 × 103 versus 30.27 ± 6.06 × 103 for FDM) and increased after 4 days of recovery (ChT: 77.94 ± 12.57 μm; ChBP: 37.41 ± 6.11 × 103). Effects of LIM were similar to those of FDM. Interocular differences in ChT and ChBP were significantly correlated in each group (FDM: R = 0.71, P < 0.001; LIM: R = 0.53, P < 0.001).

Conclusions: ChT and ChBP were significantly decreased in all three models of guinea pig myopia, and they both increased during recovery. Changes in ChT were positively correlated with changes in ChBP. Therefore, it is possible that the changes of ChT are responsible for the changes of ChBP or vice versa.
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http://dx.doi.org/10.1167/iovs.18-26397DOI Listing
July 2019

Opposing Effects of PPARα Agonism and Antagonism on Refractive Development and Form Deprivation Myopia in Guinea Pigs.

Invest Ophthalmol Vis Sci 2018 12;59(15):5803-5815

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: To determine if drug-induced peroxisome proliferator-activated receptor α (PPARα) signal pathway modulation affects refractive development and myopia in guinea pigs.

Methods: Pigmented guinea pigs were randomly divided into normal vision (unoccluded) and form deprivation myopia (FDM) groups. Each group received daily peribulbar injections of either a vehicle or (1) PPARα agonist, GW7647, clofibrate, or bezafibrate or (2) PPARα antagonist, GW6471, for 4 weeks. Baseline and posttreatment refraction and ocular biometric parameters were measured. Immunofluorescent staining of PPARα and two of its downstream readouts, cytosolic malic enzyme 1 (ME1) and apolipoproteinA II (apoA-II), was undertaken in selected scleral sections. Western blot analysis determined collagen type I expression levels.

Results: GW6471 induced a myopic shift in unoccluded eyes, but had no effect on form-deprived eyes. Conversely, GW7647 inhibited FDM progression without altering unoccluded eyes. Bezafibrate and clofibrate had effects on refraction similar to those of GW7647 in unoccluded and form-deprived eyes. GW6471 downregulated collagen type I expression in unoccluded eyes whereas bezafibrate inhibited collagen type I decreases in form-deprived eyes. GW6471 also reduced the density of ME1- and apoA-II-stained cells in unoccluded eyes whereas bezafibrate increased apoA-II-positive cell numbers in form-deprived eyes.

Conclusions: As GW7647 and GW6471 had opposing effects on myopia development, PPARα signaling modulation may be involved in this condition in guinea pigs. Fibrates are potential candidates for treating myopia since they reduced both FDM and the associated axial elongation. Bezafibrate also inhibited form deprivation-induced decreases in scleral collagen type I expression and the density of apoA-II expressing cells.
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http://dx.doi.org/10.1167/iovs.17-22297DOI Listing
December 2018

Effects of the Tyrosinase-Dependent Dopaminergic System on Refractive Error Development in Guinea Pigs.

Invest Ophthalmol Vis Sci 2018 09;59(11):4631-4638

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, State Key Laboratory of Optometry, Ophthalmology, and Vision Science, Wenzhou, Zhejiang, China.

Purpose: To determine if myopia in albino guinea pigs is linked to altered ocular dopamine (DA) levels in both the retinal and uveal dopaminergic systems.

Methods: Retina and retinal pigment epithelium (RPE)/choroid were dissected from eyes of 2-week-old albino myopic (AM) and pigmented hyperopic (PH) guinea pigs. The levels of DA, dihydroxy-phenyl acetic acid (DOPAC), and homovanillic acid (HVA) were determined. Tyrosine hydroxylase (TH) and tyrosinase activities were also measured. PH animals received daily unilateral peribulbar injections of either kojic acid (tyrosinase inhibitor) or vehicle for 2 to 4 weeks. Refractive errors and ocular axial dimensions were measured by eccentric infrared photoretinoscopy and A-scan ultrasonography.

Results: Retinal DA levels were similar between the two strains, but AM eyes had higher levels of DOPAC. RPE/choroid DA and tyrosinase activity in AM eyes were lower than in PH eyes (P < 0.01); however, the DA turnover was higher (P < 0.05). After 2 weeks of kojic acid treatment, PH eyes developed significant myopia, accompanied by elongated vitreous chambers and axial lengths. Inhibition of tyrosinase activity was linearly correlated with a myopic refraction shift (R = 0.79, P < 0.01). PH animals that received 62.5 ng/mL kojic acid treatment daily for 2 weeks followed by 625 ng/mL for 2 more weeks became more myopic and had deeper anterior chambers compared to those that received the 62.5 ng/mL dose over this period (P = 0.04).

Conclusions: The uveal tyrosinase-dependent dopaminergic system is involved in the development of guinea pig refraction. Enhancing uveal tyrosinase activity might slow down the development of myopia.
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http://dx.doi.org/10.1167/iovs.17-22315DOI Listing
September 2018

Dopamine Receptor Subtypes Mediate Opposing Effects on Form Deprivation Myopia in Pigmented Guinea Pigs.

Invest Ophthalmol Vis Sci 2018 09;59(11):4441-4448

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: We reported previously that changes in dopamine receptor (DR) subtype activation modulate spontaneous myopia progression in albino guinea pigs. To determine if DR control of refractive error development is different than in its normal counterpart, we evaluated the contribution of dopaminergic pathways to emmetropization and form deprivation myopia (FDM) progression in pigmented guinea pigs.

Methods: Monocular myopia was induced by unilateral form-deprivation (FD). The effects of agonists of D1R (SKF38393) and D2R (quinpirole), the corresponding antagonists (SCH23390 and sulpiride), and vehicle were tested by peribulbar injection around FD or untreated control eyes. High-performance liquid chromatography with electrochemical detection quantified retinal and vitreous dopamine (DA) and 4-dihydroxyphenylacetic acid (DOPAC) levels. Ocular refraction and axial dimensions were measured using eccentric infrared photoretinoscopy (EIR) and A-scan ultrasonography, respectively, initially and after 2 or 4 weeks of treatment.

Results: After treatment with any of these four agents for 2 weeks, retinal and vitreal DA and DOPAC levels were not significantly different in drug- and vehicle-treated eyes. Neither agonism nor antagonism of D1R or D2R activity affected emmetropization. In contrast, D1R activation by SKF38393 inhibited FDM progression, while D2R activation by quinpirole augmented this response. On the other hand, D2R antagonism with sulpiride slowed FDM progression while D1R antagonism with SCH23390 had no effect.

Conclusions: In pigmented guinea pigs, D1R activation inhibited, whereas D2R activation enhanced, FDM. These results closely mirror previous findings in albino animals and offer further evidence that DA and its cognate receptors affect refractive error regulation in guinea pigs.
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http://dx.doi.org/10.1167/iovs.17-21574DOI Listing
September 2018
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