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Induction of the integrated stress response in the rat cornea.

Authors
  • Peterson, C1
  • Kim, Y C2
  • Ensign, L M2
  • Jun, A S3
  • Foster, J4
  • 1 Department of Molecular & Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 4 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected]
Type
Published Article
Journal
Experimental Eye Research
Publisher
Elsevier
Publication Date
Aug 06, 2021
Pages
108722–108722
Identifiers
DOI: 10.1016/j.exer.2021.108722
PMID: 34370978
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Keratoconus (KC), a progressive, degenerative corneal disease, represents the second leading indication for corneal transplantation globally. We have previously demonstrated that components of the Integrated Stress Response (ISR) are upregulated in human keratoconic donor tissue, and treatment of normal tissue with ISR agonists attenuates collagen production. With no consistently accepted animal models available for translational KC research, we sought to establish an in vivo model based on ISR activation to elucidate its role in the development of the KC phenotype. Four-week-old female SD rats were treated with topical SAL003 formulated as a nanosuspension or vehicle every 48 hours for four doses. Animals were subject to monitoring for ocular inflammation and discomfort before being euthanized at 1, 14, or 28 days after treatment was withdrawn. Schirmer's tear test, intraocular pressure, and body weight measurements were obtained at baseline and prior to euthanasia. Globes were subject to routine histopathology, immunohistochemistry for ATF4, and qPCR for Col1a1 expression. ANOVAs and Student's t tests were used to assess statistical significance (α = 0.05). SAL003 treatment did not produce any adverse ocular or systemic phenotype but did result in decreased keratocyte density. Col1a1 transcripts were reduced, corresponding to nuclear ATF4 expression within the axial cornea. In vivo topical treatment with a gel-formulated ISR agonist recapitulates key features of the activated ISR including nuclear ATF4 expression and decreased extracellular matrix (ECM) production. Exogenous ISR agonists may present one approach to establishing a rodent model for keratoconus, a charge essential for future evaluations of pathogenesis and therapeutic interventions. Copyright © 2021. Published by Elsevier Ltd.

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