# Human Disease Modeling of Glaucomatous Neuropathy

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $161,245

## Abstract

Project Summary of Funded Grant
Glaucoma represents a group of diseases, which are associated with multiple risk factors and
genetic variants. The unifying theme among these diseases is the progressive degeneration of optic
nerve and retinal ganglion cells (RGCs) degenerate, leading to irreversible blindness. Based on
this observation we propose a hypothesis that RGCs are intrinsically vulnerable to glaucoma risk
factors and genetic variants. Since RGCs are born embryonically and glaucoma is an adult onset
disease our knowledge about the emergence of and mechanism underlying RGC susceptibility,
important for early diagnosis and formulating therapeutic approaches, remain rudimentary. Our
objective is to examine the impact of genetic variations associated with glaucoma on the
development, phenotype, and regeneration of RGCs, using the induced pluripotent stem cell
(iPSC) model of primary open angle glaucoma (POAG), the most prevalent type of the disease.
Here, we will test the hypothesis that RGCs in the SIX6 risk allele (Asn141His, rs33912345) in
POAG are developmentally compromised in normal phenotype and function, and that this affects
their survival and regeneration. The SIX6 variant is a suitable target for the analysis because SIX6
is one of the eye-field genes involved in retinal development and the missense mutation
(Asn141His) in the DNA binding region of SIX6 is accompanied by degenerative changes that
include reduction in the retinal nerve fiber layer (RNFL) thickness in POAG. Thus, the generation
of SIX6 risk allele-POAG RGCs in a dish model of the disease would allow the characterization
of developmental and phenotype abnormalities, shedding light on glaucomatous RGC
susceptibility. We have proposed three aims to test the central hypothesis. First, we will determine
the impact of the SIX6 risk allele-POAG on the development and phenotype of patient-specific
RGCs by systematic characterization of sequential steps of retinal inductions and RGC
differentiation of POAG patient-specific and age- and sex-matched control iPSCs, under the
influence of a stage-specific and chemically defined protocol. Second, we will examine the impact
of the SIX6 risk allele-POAG on patient-specific RGC axon growth and regeneration in the context
of mTOR signaling, a regulator of retinal development and regeneration, which is inhibited in
POAG patient-specific RGCs. Lastly, we will identify the molecular pathway(s) underlying
abnormal RGC development and phenotype. We will carry out hypothesis-driven (e.g., HMGA2
and KLF-4 as candidate hub genes) genome wide transcriptional analysis of POAG patient-specific
RGCs during development and regeneration to understand the molecular mechanism underlying
SIX6 risk allele associated RGC abnormalities. Information emerging from our study will bridge
a gap in our knowledge of the intrinsic vulnerability of RGCs in glaucoma. The information on
dysregulated processes and pathways will reveal biomarkers for early diagnosis, ...

## Key facts

- **NIH application ID:** 10152244
- **Project number:** 3R01EY029778-02S1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Iqbal Ahmad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,245
- **Award type:** 3
- **Project period:** 2019-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152244

## Citation

> US National Institutes of Health, RePORTER application 10152244, Human Disease Modeling of Glaucomatous Neuropathy (3R01EY029778-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152244. Licensed CC0.

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