# Regulation of successful optic nerve regeneration by the mevalonate/cholesterol pathway

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $351,000

## Abstract

PROJECT SUMMARY
Loss of vision due to optic neuropathies, like glaucoma, is a common cause of blindness in the United States.
Unfortunately, these conditions are usually permanent because the central nervous system lacks the ability to
regenerate damaged axons. Mammalian models of optic nerve (ON) injury recapitulate the pathology seen in
patients making it difficult to understand what is needed for successful regeneration. In contrast, teleost fish,
such as the zebrafish, can successfully regenerate damage to the ON and recover lost vision. We are using this
organism to study the mechanisms of successful ON regeneration with the hopes of translating these findings
into novel therapeutics to improve regeneration in mammalian disease models and patients. In a transcriptome-
wide study of retinal ganglion cells (RGCs) during zebrafish ON regeneration we identified the mevalonate and
cholesterol pathways as up regulated during this process. Our preliminary data suggests the master
transcriptional regulator of these pathways, srebf2, is necessary for successful ON regeneration. We hypothesize
that srebf2 mediates ON regeneration by activating the RGC intrinsic mevalonate and cholesterol synthesis
pathway and/or inducing expression of receptors for extracellular sources of cholesterol and lipids. Using the
powerful genetic and chemical tools available for the zebrafish system, we propose to identify the critical period
of srebf2 activity and the downstream mediator(s) of its function. Aim 1 will determine when srebf2 function in
RGCs is critical for ON regeneration and using novel reporter lines of srebf2 activity to delineate when
transcriptional activity occurs. We will also test if activation of srebf2 activity is sufficient to accelerate ON
regeneration. Lastly, we will use laser capture microdissection RNA-seq (LCM-seq) to identify differential gene
expression under gain- and loss-of-srebf2 function in RGCs. Aim 2 proposes to identify which RGC intrinsic or
extrinsic pathways downstream of srebf2 mediate its function. We will use combinations of drugs and gene
knockdown to determine if intrinsic mevalonate/cholesterol synthesis and external supplies are independent,
interdependent, and/or compensatory for successful ON regeneration. Depending upon the results of this study
we will further examine the downstream intrinsic synthesis pathways for cholesterol, ubiquinone, protein
prenylation, and protein N-glycosylation or low-density lipoprotein receptors and their downstream processing.
Aim 3 will test the sufficiency of Srebf2 expression to provide neuroprotection and stimulate axon regeneration
in a mouse model of acute ON injury. LCM-seq will be used to identify gene expression changes induced in
mouse RGCs by Srebf2 and compared to those identified in zebrafish to suggest mechanisms for success or
failure. These experiments will delineate the pathways downstream of srebf2 necessary for efficient ON
regeneration and suggest paths forward to enha...

## Key facts

- **NIH application ID:** 10817943
- **Project number:** 5R01EY034097-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Matthew B Veldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817943

## Citation

> US National Institutes of Health, RePORTER application 10817943, Regulation of successful optic nerve regeneration by the mevalonate/cholesterol pathway (5R01EY034097-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10817943. Licensed CC0.

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