# Molecular Regulation of Photoreceptor Cell Death

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $592,048

## Abstract

ABSTRACT
 Retinal diseases are a leading cause of blindness, tremendously impacting patients and society. A root
cause of poor vision is death of the photoreceptor cell, which primarily results from disruption of the normal
homeostatic interaction between these cells and the underlying retinal pigment epithelium (RPE). Preserving
photoreceptor (PR) viability and function remains a critical unmet medical need. PRs have the highest oxygen
consumption in the body. The choroidal vasculature supplies this demand through the RPE – a process that
requires close apposition and intimate interaction. Periods of disrupted retina-RPE homeostasis might be
expected to result in marked and rapid PR cell death. However, PRs can survive periods of reduced RPE
nutritional support, resulting in a clinical window of opportunity for treating retinal disease. Currently there are
no therapeutic options to maintain PR viability or slow the rate of cell death to extend this treatment window. In
experimental retinal detachments (RD), a validated model of altered PR-RPE homeostasis, we have found
activation of both pro-survival and death pathways. Examples of the former include the release of protective
cytokines and activation of autophagy; whereas cell death occurs primarily through Fas-mediated apoptosis. A
major gap in our knowledge is that we do not know the upstream activators of these cytoprotective and
cytodestructive pathways. We hypothesize that HMGB1 and microglia represent key intrinsic and extrinsic
influences, respectively. Our preliminary data strongly point towards a role for the multifunction protein known
as High-Mobility Group Box 1 (HMGB1) in the intrinsic protection of PR and the innate immune response to
stressed PR. In Specific Aim 1 we will define the role of HMGB1 in PR death and activation of retinal microglia
after RD and in a model of inherited retinal degeneration. Our preliminary data connects the upregulation of
HMGB1 in rod PR to protective autophagy and the activation of microglia following RD. We will investigate the
function of cytosolic HMGB1 in cell-autonomous activation and stabilization of pro-survival pathways within
PRs and the function of released HMGB1 to promote microglial activation. In Specific Aim 2 we will determine
the role of microglia in the inflammatory response and PR death following RD. The relative contributions of
microglia and infiltrating myeloid leukocytes and how the immune response affects PR survival are not clear.
Based on our preliminary data, we hypothesize that resident microglia are the major first responders to RD,
and that microglia are initially protective but eventually shift to a detrimental inflammatory phenotype. We
further hypothesize that the p38a-ULK1 axis contributes to this shift. We will define and characterize the
immune cells responding to RD and test if targeting p38a and promoting autophagy are protective following
RD. The work proposed in this grant will provide a critical understanding of...

## Key facts

- **NIH application ID:** 10149320
- **Project number:** 5R01EY020823-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Steven F Abcouwer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,048
- **Award type:** 5
- **Project period:** 2010-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149320

## Citation

> US National Institutes of Health, RePORTER application 10149320, Molecular Regulation of Photoreceptor Cell Death (5R01EY020823-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10149320. Licensed CC0.

---

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