# Regulation of retinopathies

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $390,425

## Abstract

Diabetic retinopathy is a major cause of blindness in the United States. Increased expression of
inflammatory molecules and death of retinal endothelial cells (capillary degeneration) with resulting
local retinal ischemia are believed to be important for development of this disease. We uncovered
CD40 as a major driver of the upregulation of inflammatory molecules in the retina and development
of capillary degeneration in experimental diabetic retinopathy. In addition, CD40 in Müller cells triggers
purinergic signaling (ATP-P2X7) that drives expression of pro-inflammatory cytokines in by-stander
microglia/macrophages and programmed cell death of retinal endothelial cells.
 [VEGF upregulation is an event central to capillary leakage and retinal neovascularization in
diabetic retinopathy. VEGF upregulation in the diabetic retina is driven by activation of the Unfolded
Protein Response (UPR) in Müller cells. However, we have an incomplete understanding on how UPR
is activated in the disease.]
 The objective of this application is to further our understanding of the [induction of UPR, the
upregulation of VEGF] and inflammatory molecules in diabetic retinopathy. The central hypothesis is
that a specific signaling pathway downstream of CD40 controls [UPR, VEGF upregulation and the
ATP-P2X7 cascade such that selective blockade of this pathway will prevent UPR, VEGF
upregulation,] inflammatory molecule upregulation, capillary degeneration and will protect against
experimental diabetic retinopathy. [In the first aim we will examine how CD40 stimulates UPR in
Müller cells. In the second aim we will determine if CD40 upregulates VEGF via UPR and whether the
signaling pathway that mediates UPR/VEGF upregulation is different from the pathway that causes
direct upregulation of inflammatory molecules in Müller cells. Both aims will be pursued using genetic
approaches that block specific signaling pathways.] In the third aim we will use an animal model of
experimental diabetic retinopathy and transgenic mice to determine if [CD40 drives UPR and VEGF
upregulation in vivo and whether genetic blockade of an upstream event in CD40 signaling impairs
upregulation of UPR, VEGF and various inflammatory molecules in the diabetic retina.] Using similar
methodologies, in the fourth aim we will test the in vivo effects of a specific inhibitor of CD40 signaling
in the induction of the events described above. [The proposed work will further our understanding of
UPR/VEGF upregulation in diabetic retinopathy] and may lead to further development of selective
inhibitors of CD40 signaling as a novel approach for treatment of diabetic retinopathy.

## Key facts

- **NIH application ID:** 10132320
- **Project number:** 5R01EY019250-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** CARLOS S SUBAUSTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,425
- **Award type:** 5
- **Project period:** 2010-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132320

## Citation

> US National Institutes of Health, RePORTER application 10132320, Regulation of retinopathies (5R01EY019250-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10132320. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*