# Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $467,301

## Abstract

Diabetic retinopathy is clinically defined as a disease of the retinal microvasculature, and most
research on its pathogenesis to date has focused on molecular and metabolic defects within the
blood vessel cells themselves. In recent years, we have provided evidence that cells in the
outer retina play a critical role the development of diabetic retinopathy. The current application
will investigate the hypothesis that visual cycle activity plays a key role in initiation of the
degenerative vascular lesions in early stages of diabetic retinopathy, and does this by
increasing oxidative stress and inflammation within rod photoreceptors. Ultimately, the stressed
photoreceptors release soluble factors (including cytokines) that damage the vasculature
secondary to activating circulation leukocytes. Thus, the central hypothesis of our proposal is
that hyperglycemia or other abnormalities that stress photoreceptors (such as rhodopsin
mutants) lead to generation superoxide and other reactive products, and that these
abnormalities initiate the structural and functional changes of the microvasculature which are
clinically recognized as early diabetic retinopathy.
Specific Aims will be: (1) to evaluate the roles of visual cycle activity in the retinal capillary
damage caused by diabetes., (2) to investigate the roles of oxidative stress and/or inflammation
within photoreceptors to initiate damage to the retinal vasculature, and (3) to identify soluble
factors released by photoreceptors in diabetes, and mechanism by which those factors
contribute to retinal capillary damage. The research proposed in Aim 1 will use mouse models in
which RPE65 and LRAT are deficient, as well as a novel inhibitor of RPE65 to assess visual
cycle activity. Aim 2 will be tested using mice having (i) photoreceptor-specific knockdown of
activities of NADPH oxidase activity and NF-ĸB activation. Diabetes will be induced
experimentally in male and female mice. This is a highly novel and testable hypothesis that will
be conducted by an experienced research team. Confirmation of retinal photoreceptor cells as
contributors to retinal capillary disease in DR (and other retinal vascular diseases) will offer
several novel approaches to inhibit the development of these retinopathies.

## Key facts

- **NIH application ID:** 10169449
- **Project number:** 5R01EY022938-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Timothy S Kern
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,301
- **Award type:** 5
- **Project period:** 2013-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169449

## Citation

> US National Institutes of Health, RePORTER application 10169449, Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy (5R01EY022938-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169449. Licensed CC0.

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