# Metabolic Reprogramming for Photoreceptor Neuroprotection

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $378,300

## Abstract

PROJECT SUMMARY
 A key gap remains in our ability to develop successful treatment strategies to prevent photoreceptor
(PR) loss and restore vision. To address this gap, we are proposing novel strategies to reprogram metabolism
and boost PR survival. PRs have unique metabolic adaptations and utilize aerobic glycolysis to budget their
metabolic needs based on nutrient availability, balancing the synthesis of amino acid, nucleotide and lipid
precursors with energy generation. PRs perform aerobic glycolysis by expressing hexokinase 2 (HK2) and
pyruvate kinase muscle 2 (PKM2). HK2, the first enzyme of glycolysis, acts as an intracellular rheostat, a
unique non-enzymatic function that links metabolic status to survival by regulating apoptosis and autophagy.
PKM2 is the gatekeeper of energy metabolism and controls aerobic glycolytic flux. HK2 expression is critical
for the survival of PRs, as replacing HK2 with HK1 isoform increases apoptosis after stress. Furthermore,
replacing low-activity PKM2 with its high-activity isoform PKM1 increases total PKM activity in PRs and boosts
survival after nutrient deprivation. The over-arching hypothesis of this proposal is that metabolic
reprogramming of PRs, by modulating HKs and PKMs, will enhance survival of stressed PRs, enzymatically by
increasing energy generation via glycolysis, and non-enzymatically by inhibiting death signals during energy
crisis. The objectives in this project are to: 1) utilize genetic and pharmacologic manipulation of PKM and HK
function and prevent retinal detachment induced PR death by metabolic reprograming; and 2) identify non-
enzymatic functions of HKs that regulate PR survival during experimental retinal detachment.
 Aim 1: To test the hypothesis that augmenting energy homeostasis by altering PKM function
will enhance PR survival during stress. Our hypothesis predicts that increasing total PKM activity provides
survival advantage during apoptotic stress by shifting PR metabolism to more efficiently generate ATP from
limited energy substrates. These studies will measure glycolytic flux, ATP generation, and cell death in an
acute PR stress model upon Pkm1 overexpression or pharmacologic activation of PKM2.
 Aim 2: To test the hypothesis that HK2 is the molecular rheostat that links metabolic status to
PR apoptosis and autophagy. Our hypothesis predicts that HK2 links PR metabolic needs to survival and
that HK2 to HK1 reprograming will decouple metabolic regulation of apoptosis and autophagy. These studies
will identify the links between HK2 and key regulators of apoptosis and autophagy in PRs and will measure the
effect of HK2 to HK1 reprogramming on glycolysis, biosynthesis, and PR cell death.
 Our approach is innovative as we will connect the unique energy metabolism of PRs directly to cell
death regulation via manipulating the key mediators of aerobic glycolysis, i.e. PKM2 and HK2. The proposed
research is significant in that it will provide critical information on how unique me...

## Key facts

- **NIH application ID:** 10200068
- **Project number:** 5R01EY029675-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Cagri Besirli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,300
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200068

## Citation

> US National Institutes of Health, RePORTER application 10200068, Metabolic Reprogramming for Photoreceptor Neuroprotection (5R01EY029675-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200068. Licensed CC0.

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