Induction of the integrated stress response in the rat cornea

Peterson, Curt M.; Kim, Y.C.; Ensign, Laura M.; Jun, Albert S.; Foster, James W.

doi:10.1016/j.exer.2021.108722

Cited by 3 publications

(8 citation statements)

References 38 publications

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“…ATF4 is a transcription factor activated during ISR that regulates the expression of genes targeted by stress induction [87]. Increased activation of this transcription factor in the nucleus indicates that ISR is activated [41]. The study does not mention any morphological changes to the cornea, such as a cone-like shape [41].…”

Section: Treatment-induced Rat Modelsmentioning

confidence: 97%

“…Increased activation of this transcription factor in the nucleus indicates that ISR is activated [41]. The study does not mention any morphological changes to the cornea, such as a cone-like shape [41]. The authors do acknowledge that further keratometric assessment is required [41].…”

Section: Treatment-induced Rat Modelsmentioning

confidence: 98%

“…Furthermore, there are no genetic or spontaneous models. Multiple experiments report inducing some degree of KC in rats using a variety of treatments, including UVR, SAL003, and vitamin A deficiency [40][41][42].…”

Section: Rat Modelsmentioning

confidence: 99%

“…Previously, it was revealed that human keratoconus fibroblasts upregulated ISR compared to human control fibroblasts [86]. After treatment with SAL006, the rat corneas showed reduced stromal keratocyte density, decreased collagenous extracellular matrix production, and the induction of nuclear ATF4 [41]. ATF4 is a transcription factor activated during ISR that regulates the expression of genes targeted by stress induction [87].…”

Section: Treatment-induced Rat Modelsmentioning

confidence: 99%

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Animal Models for the Study of Keratoconus

Hadvina,

Estes,

Liu

2023

Cells

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Keratoconus (KC) is characterized by localized, central thinning and cone-like protrusion of the cornea. Its precise etiology remains undetermined, although both genetic and environmental factors are known to contribute to disease susceptibility. Due to KC’s complex nature, there is currently no ideal animal model to represent both the corneal phenotype and underlying pathophysiology. Attempts to establish a KC model have involved mice, rats, and rabbits, with some additional novel animals suggested. Genetic animal models have only been attempted in mice. Similarly, spontaneously occurring animal models for KC have only been discovered in mice. Models generated using chemical or environmental treatments have been attempted in mice, rats, and rabbits. Among several methods used to induce KC in animals, ultraviolet radiation exposure and treatment with collagenase are some of the most prevalent. There is a clear need for an experimental model animal to elucidate the underlying mechanisms behind the development and progression of keratoconus. An appropriate animal model could also aid in the development of treatments to slow or arrest the disorder.

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Section: Treatment-induced Rat Modelsmentioning

confidence: 97%

Section: Treatment-induced Rat Modelsmentioning

confidence: 98%

Section: Rat Modelsmentioning

confidence: 99%

Section: Treatment-induced Rat Modelsmentioning

confidence: 99%

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Animal Models for the Study of Keratoconus

Hadvina,

Estes,

Liu

2023

Cells

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“…Our previous publications have identified activation of the ISR in the cornea of keratoconic patients and have highlighted the effects on cellular phenotype both in vitro and in vivo. 11 , 13 , 14 Moreover, there is an extensive body of work regarding the activation of this pathway in the eye and other tissues that warrants further investigation in the corneal epithelium. 2 , 3 , 15 , 16 The purpose of these studies was to characterize and dissect the response of corneal epithelial cells to ISR challenge.…”

mentioning

confidence: 99%

Integrated Stress Response Regulation of Corneal Epithelial Cell Motility and Cytokine Production

Chu

Peterson

Chamling

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose To investigate the effect of an active integrated stress response (ISR) on human corneal epithelial cell motility and cytokine production. Methods ISR agonists tunicamycin (TUN) and SAL003 (SAL) were used to stimulate the ISR in immortalized corneal epithelial cell lines, primary human limbal epithelial stem cells, and ex vivo human corneas. Reporter lines for ISR-associated transcription factors activating transcription factor 4 (ATF4) and XBP1 activity were generated to visualize pathway activity in response to kinase-specific agonists. Scratch assays and multiplex magnetic bead arrays were used to investigate the effects of an active ISR on scratch wounds and cytokine production. A C/EBP homologous protein (CHOP) knockout cell line was generated to investigate the effects of ISR ablation. Finally, an ISR antagonist was assayed for its ability to rescue negative phenotypic changes associated with an active ISR. Results ISR stimulation, mediated through CHOP, inhibited cell motility in both immortalized and primary human limbal epithelial cells. Scratch wounding of ex vivo corneas elicited an increase in the ISR mediators phosphorylated-eIF2α and ATF4. ISR stimulation also increased the production of vascular endothelial growth factor (VEGF) and proinflammatory cytokines. ISR ablation, through CHOP knockout or inhibition with integrated stress response inhibitor (ISRIB) rescued epithelia migration ability and reduced VEGF secretion. Conclusions We demonstrate that the ISR has dramatic effects on the ability of corneal epithelial cells to respond to wounding models and increases the production of proinflammatory and angiogenic factors. Inhibition of the ISR may provide a new therapeutic option for corneal diseases in which the ISR is implicated.

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