# Defining the Extrinsic and Intrinsic Mechanisms of Vision Loss in Optic Glioma

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2024 · $178,918

## Abstract

Project Summary
This proposal is a five-year career development plan that will support my transition to an independent career as
a neuroscientist and neuro-ophthalmologist focused on understanding the mechanisms of neurodegeneration in
the visual system and developing therapies for vision restoration. I am currently an Instructor in the Department
of Neurology. Under the mentorship of Dr. David Gutmann, MD, PhD, and with the guidance of my scientific
advisory committee, I will receive didactic and practical training to expand my scientific and clinical expertise, as
well as improve my skills in collaboration, communication, lab management, grantsmanship, and leadership
needed for an independent scientific career. In addition, I will build upon my preliminary experiments to delineate
the mechanisms underlying estrogen-mediated (extrinsic) and cyclic-AMP (cAMP)-mediated (intrinsic)
vulnerability of retinal ganglion cells (RGCs) that collectively culminate in RGC death and vision loss in an
authenticated mouse model of optic pathway glioma (OPG).
Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome in which 15-20% of children develop an
OPG, a low-grade astrocytoma of the visual pathway. Of these affected children, 30-50% will experience vision
loss due to RGC death. Moreover, girls with NF1-OPG are 3-5 times more likely to require treatment due to
vision loss than boys, despite a relatively equal incidence of OPGs in both sexes. These findings suggest that
vision loss from NF1-OPG is controlled by mechanisms that are sexually dimorphic. Leveraging authenticated
mouse models of Nf1-OPG developed by the Gutmann laboratory, I identified estrogen-activated glial production
of interleukin 1β (IL-1β) as a possible extrinsic mechanism for RGC death due to Nf1-OPG. Building upon
previous findings demonstrating that defective cAMP production predisposes Nf1-mutant RGCs to injury, I also
identified cAMP-dependent protein kinase inhibitor α (PKIα) as a potential mediator of the intrinsic RGC
vulnerability in the setting of Nf1-OPG. Based on these exciting preliminary results, I hypothesize that estrogen-
mediated glial expression of IL-1β is neurotoxic to Nf1-mutant RGCs with a pre-existing vulnerability to death
conferred by reduced cAMP-dependent survival signaling. In this proposal, I have designed experiments to (1)
define the necessity of estrogen-induced IL-1β in Nf1-OPG-mediated RGC death, (2) determine whether PKA
inhibition heightens RGC vulnerability in the setting of Nf1-OPG, and (3) execute preclinical studies to evaluate
estrogen suppression and cAMP restoration as potential neuroprotective strategies. The goals of the proposed
experiments aim to (1) expand our understanding of molecular mechanisms underlying RGC death and vision
loss in Nf1-OPG, (2) identify targets for the development of vision restorative therapies for children with vision
loss due to NF1-OPG, and (3) lay the groundwork for my future studies and career developmen...

## Key facts

- **NIH application ID:** 10985287
- **Project number:** 1K08NS133966-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Yunshuo Caroline Tang
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $178,918
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985287

## Citation

> US National Institutes of Health, RePORTER application 10985287, Defining the Extrinsic and Intrinsic Mechanisms of Vision Loss in Optic Glioma (1K08NS133966-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985287. Licensed CC0.

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