# Development and Maintenance of the Human Photoreceptor-Bipolar Cell Synapse.

> **NIH NIH K08** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $221,206

## Abstract

Project Summary
The first synapse of the visual system—between photoreceptors and bipolar cells—is critical to visual processing
but displays abnormal specificity and maintenance in the setting of photoreceptor dysfunction. Functional
restoration, for example with gene or cell-based therapies, will depend upon a greater understanding of altered
synaptic connectivity in human retinal disease. The human retinal organoid system permits the detailed study
of synaptic development and maintenance in retinal tissue in a scalable and experimentally accessible fashion.
The proposed experiments will use human retinal organoids to address the hypothesis that rod bipolar cell (RBC)
dendrites initially form non-specific contacts with rods and cones, which then become increasingly specific during
development, and that synaptic promiscuity in retinal diseases represents a recapitulation of these non-specific
interactions in early retinal development. This hypothesis will be tested in three Specific Aims. Aim 1 determines
the long-term developmental stages of photoreceptor-bipolar cell synaptogenesis and specifically examines
whether rod-RBC synaptic specificity is achieved by pruning inappropriate contacts. Aim 2 investigates the
short-term dynamics of RBC synaptogenesis in live organoids using a CRISPR-engineered fluorescent reporter
line to ascertain whether exploratory dendrite behavior facilitates synaptic specificity. Aim 3 examines the role
of glutamate release in synapse formation, maintenance, and specificity as mediated by Cav1.4, the presynaptic
calcium channel implicated in X-linked congenital stationary night blindness. The proposed work will provide
opportunities to make significant advances in understanding synaptic wiring in human retinal tissue, thus
establishing this system to identify molecular targets that maintain or restore synaptic connectivity. This
application constitutes the foundation of my career development award (K08) as an academic pediatric retina
specialist with very high motivation and institutional support to develop an independent laboratory research
program in pediatric retinal disease. In pursuit of these aims, I will be mentored by renowned scientists at
Children's Hospital Los Angeles and the University of Southern California, as I gain the necessary skills in human
retinal organoid techniques, retinal and synaptic neuroscience, and live cell imaging to achieve independence
through R01 funding. Ultimately, my work will explore for the first time human retinal synaptic connectivity during
development and establish a research program focused on restoring these connections in the human disease
state.

## Key facts

- **NIH application ID:** 9869742
- **Project number:** 1K08EY030924-01
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Aaron Nagiel
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,206
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869742

## Citation

> US National Institutes of Health, RePORTER application 9869742, Development and Maintenance of the Human Photoreceptor-Bipolar Cell Synapse. (1K08EY030924-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869742. Licensed CC0.

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