June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Htra1 KO mice develop severe photoreceptor loss and RPE abnormalities.
Author Affiliations & Notes
  • Pooja Biswas
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Anne Marie Berry
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Shikha Pachauri
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Manisha Dagar
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Naheed W Khan
    Ophthalmology and Visual Sciences, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Peter Shaw
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Donita Garland
    Harnly LLC, Bethesda, Maryland, United States
  • Monica M Jablonski
    Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Radha Ayyagari
    Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Footnotes
    Commercial Relationships   Pooja Biswas None; Anne Marie Berry None; Shikha Pachauri None; Manisha Dagar None; Naheed Khan None; Peter Shaw None; Donita Garland None; Monica Jablonski None; Radha Ayyagari None
  • Footnotes
    Support  The Foundation Fighting Blindness, Research to Prevent Blindness, The Nixon Visions Foundation, NIHRO1EY21237, R01EY030591, RO1EY031663, T32EY026590, P30-EY22589
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1592 – A0381. doi:
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    • Get Citation

      Pooja Biswas, Anne Marie Berry, Shikha Pachauri, Manisha Dagar, Naheed W Khan, Peter Shaw, Donita Garland, Monica M Jablonski, Radha Ayyagari; Htra1 KO mice develop severe photoreceptor loss and RPE abnormalities.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1592 – A0381.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : High-temperature requirement protein A1 (HTRA1) is a serine protease secreted by a number of tissues including the retinal pigment epithelium (RPE). The purpose of this study was to characterize the retinal phenotype of an Htra1 gene knock-out (Htra1-/-) mouse model to understand the role of HTRA1 in retinal pathology.

Methods : The ocular phenotype of these Htra1-/- mice was studied by evaluation of gross morphology, fundus imaging, and electroretinography (ERG) at ages 5 and 19 months. For further evaluation, retinal morphology and expression of relevant marker genes and proteins were evaluated by immunohistochemistry (IHC) and quantitative real time PCR (qRT-PCR) of 19 months old Htra1-/- mice and compared with age matched controls.

Results : ERG responses in the Htra1-/- mice were highly reduced compared to wildtype mice as early as 5 months and progressed until 19 months. A significant loss of short wavelength cones (p<0.0001) and medium wavelength cones (p<0.0001) was observed in Htra1-/- mice compared to the age-matched controls by IHC at 19 months. A significant reduction in the level of expression of Opn1sw/S-opsin (p=0.0002), Opn1mw/M-opsin (p=0.0002) and Rho/Rhodopsin (p=0.0002) transcripts was noted at 19 months by qRT-PCR. In addition, the expression of HTRA1 protein was not detected in Htra1-/- mice retina. A significant increase in the expression of other macular degeneration (MD) associated genes, C1qtnf5/Ctrp5 (p=0.0008), Timp3 (p<0.0001) and Efemp1 (p=0.0008) were observed in Htra1-/- mouse by qRT and IHC at 19 months. Whereas expression of the RPE markers ZO1 (p=0.0023) and MERTK are significantly lower at 19 months. Progressive accumulation of auto-fluorescent spots close to retinal vessels were observed at 5 months and 19 months of age. Evaluation of retinal phenotype including ultrastructure analysis by electron microscopy (EM) at multiple younger ages is in progress.

Conclusions : The Htra1-/- KO mice showed loss of photoreceptors, decrease in the expression of rod, cone, and RPE markers and abnormal photoreceptor function. In addition, accumulation of extra cellular matrix (ECM) components associated with MD phenotype was also noted suggesting a possible role for HTRA1 in retinal and macular degeneration pathology.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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