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NIH grant 1I01RD001109-01A1: Stem Cells to Retina: METTL3 at the Nexus of the Epitranscriptome andEpigenome
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Rajesh C. Rao. Award: $.
Start: 2026-10-01T00:00:00.
Significance to VA: Age-related macular degeneration (AMD), diabetic retinopathy, glaucoma, and combat-
related eye trauma are major causes of irreversible vision loss in Veterans, affecting ~1 in 10 U.S. Veterans.
These conditions, linked to the loss of retinal neurons like retinal ganglion cells (RGCs) and photoreceptors,
lack therapies to restore vision once cells are lost. With ~5M annual VA visits and rising costs, these diseases
pose a significant burden. This study addresses unmet needs in Veteran eye care by exploring epitran-
scriptomics to uncover mechanisms controlling stem cell differentiation into retinal cells, informing novel cell
therapies and regenerative strategies for vision restoration.
Innovation and Impact: This proposal pioneers epitranscriptomics in vision science, focusing on METTL3 and
METTL14, key components of the m6A methyltransferase complex (MTC), which methylates 20-40% of RNA.
We discovered METTL3 regulates pluripotent stem cell (PSC) differentiation into retinal progenitor cells, RGCs,
and photoreceptors, linking the epitranscriptome to the epigenome via histone modifications and a novel
METTL3-HAT1 interaction. Using cutting-edge tools like quantitative m6A mapping (GLORI) and dCas13b-
FTO engineering, we aim to elucidate non-canonical roles of METTL3 and identify therapeutic targets (e.g.,
Ythdf1, Zfp292). These insights will advance cell therapy and in situ regeneration for AMD, glaucoma, and ocu-
lar trauma, addressing critical Veteran health needs.
Specific Aims:
1. Map METTL3-dependent m6A roles in retinal development using GLORI and dCas13b-FTO engineer-
ing.
2. Investigate METTL3-driven epitranscriptomic-epigenomic crosstalk via METTL3-HAT1 interactions and
H3K9Ac/H3K4me3 mapping.
3. Identify MTC functional targets (e.g., Zfp292) in Mettl3/Mettl14-deficient retinal progenitor cells using
eCLIP and RNA-seq.
Methodology: We will use PSC-derived retinal organoids and animal models, employing GLORI for m6A map-
ping, CUT&RUN and ATAC-seq for epigenomic analysis, and eCLIP for protein-RNA interactions. Cas9 and
Cas13b-based editing will validate targets in vitro and in vivo.
Path to Translation: We are focused on a stage of the VA-ORD Translational Pipeline Stage T0: “T0-1B: De-
veloping / evaluating novel approach/strategy to address unmet clinical need.” Through a retinal organoid plat-
form, we will identify METTL3 modulators and its RNA targets (Ythdf1/Zfp292) with the goal to enhance cell
therapy from PSCs and identify novel pathways for in situ regeneration. Promising candidates will advance to
animal model testing and eventual clinical trials, addressing the lack of vision-restoring therapies for Veterans
with retinal disease.document fetched 2026-10-26 02:47