# Elucidating the role of pioneer factors in RPC developmental competence

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Temporal patterning drives retinal cellular diversity through complex gene regulatory networks (GRNs). These
GRNs are headed by transcription factors (TFs) that promote stage-specific cell birth while repressing GRNs
associated with other developmental timepoints. This cross play is especially noticeable when comparing the
GRNs controlling generation of early and late-born cell types in retinal progenitor cells (RPCs). Notably, over
the course of differentiation, mammalian retinal cells lose the regenerative capacity seen in fish and amphibian
models. This loss of regenerative capacity permits for the cell death associated with leading causes of
blindness such as age-related macular degeneration and glaucoma. Key to therapeutic interventions is an
understanding of how to stimulate the birth of specific cell types to allow for successful regrowth of the cell
populations damaged in the course of these diseases. This understanding hinges on identifying which TFs
within the GRNs drive cell fate specification and the loss of pluripotency for the early and late-stage RPCs.
Because the genomic organizational states between the early and late-stage RPCs is so distinct, I
hypothesize that the TFs driving the GRNs act in a pioneering capacity to drive the birth of temporally
restricted cell types. If this holds true, the TFs associated with early-born cell types will be able to drive the
birth of cones, amacrines, and horizontal cells in late-stage RPCs through the opening of genomic regions
inaccessible at that temporal window. Likewise, late-stage TFs will induce the production of bipolar cells and
Müller glia in the early RPC population through genomic organizational changes. To address these
hypotheses, I propose two Aims. Aim 1: Functional analysis of top candidate transcription factors for temporal
patterning regulation. This work will help me narrow down the list of candidate regulators of temporal patterning
through validation of their impact on cell fate in gain-of and loss-of-function experiments in the developing
mouse retina. Aim 2: Determine whether TFs that regulate transition from early to late-stage states have
pioneering activity. I will take established temporal patterning regulators and assay how they control the
dynamics of epigenetic modulation. Once systems for in vitro and in vivo characterization have been
established, I will take candidates identified in Aim 1 and use this pipeline to phenotype their pioneering
activity. Through the establishment of a set of PFs that drive early and late-stage cell fate specification in the
retina, I will be able to better address current barriers to successful iPSC-derived cell-based therapeutic
approaches to glaucoma and age-related macular degeneration.

## Key facts

- **NIH application ID:** 10313677
- **Project number:** 1F31EY033207-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Patrick Leavey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-08-29 → 2024-08-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313677

## Citation

> US National Institutes of Health, RePORTER application 10313677, Elucidating the role of pioneer factors in RPC developmental competence (1F31EY033207-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313677. Licensed CC0.

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