# Cell specific roles of the endothelin system in glaucoma-relevant retinal ganglion cell death

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $502,883

## Abstract

Glaucoma is an optic neuropathy characterized by retinal ganglion cell (RGC) death and optic nerve
degeneration. Unfortunately, there are no current treatments that specifically target neurodegeneration.
Identifying the signaling pathways responsible for disease onset and progression will be an important step in
developing effective pharmacologic interventions for glaucomatous neurodegeneration. The endothelin (EDN)
system is widely expressed throughout the body and participates in both physiological and pathophysiological
processes. There is now a large body of evidence implicating the EDN system in human and in animal models
of glaucoma. Manipulation of the EDN system significantly lessens RGC loss in a genetic and two inducible
models of glaucoma. Also EDN signaling is upregulated in both the retina and optic nerve head prior to any
signs of RGC death or dysfunction in an ocular hypertensive model of glaucoma. Despite the potential
importance of EDN in glaucomatous neurodegeneration, the molecular mechanisms of EDN-induced RGC
death are completely undefined. In particular, the upstream regulators and the downstream effectors of the
EDN system are not known. Contributing to the difficulty in understanding how EDN signaling plays a role in
glaucomatous neurodegeneration is the fact that EDN receptors, Ednra and Ednrb, are expressed on
numerous cell types in the retina and optic nerve head including RGCs, astrocytes, myeloid derived cells
(microglia and macrophages), and mural cells (pericytes and smooth muscle vascular cells). Furthermore,
EDN is known to affect all of these cells in ways that are consistent with pathological responses observed in
glaucoma. Thus, in order to understand EDN signaling in glaucoma the requirement of components of the EDN
system, both receptors and ligands, must be systematically tested in the glaucoma-relevant cells they are
expressed in. Here, we will test the hypothesis that defining the role of the EDN system in RGC death will
identify early, critical signaling pathways that underlie glaucoma pathogenesis. To accomplish this and to
define how EDN signaling functions after glaucoma-relevant insults, we will 1) define the mechanisms within
RGCs that are required for EDN-induced RGC death, 2) determine the receptor, cell type, and molecular
pathway(s) controlling EDN-induced RGC death, and 3) determine which cell types and molecular pathways
are responsible for producing pathogenic EDN ligands. Importantly, this application will focus on the role of the
EDN system in individual cell types, conditionally removing EDN components and performing transcriptomics
on individual cell types. Together, the experiments outlined in the application critically test a long-standing
hypothesis about the role of EDN in glaucoma and identify the various cell types and molecular mechanisms
controlling glaucoma-relevant pathogenic EDN signaling. Given the early nature and proven role of EDN
signaling in glaucomatous neurodegeneration ...

## Key facts

- **NIH application ID:** 10132328
- **Project number:** 5R01EY027701-05
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gareth R Howell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,883
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132328

## Citation

> US National Institutes of Health, RePORTER application 10132328, Cell specific roles of the endothelin system in glaucoma-relevant retinal ganglion cell death (5R01EY027701-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132328. Licensed CC0.

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