# Phototransduction in health and disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $559,444

## Abstract

Abstract
Cyclic GMP and calcium (Ca2+) are effectors of phototransduction and maintenance of their homeostasis is
critical for photoreceptor cell health and function. Indeed, perturbance of this homeostasis is thought to be a
primary driver of cell death in different forms of retinal degenerations. For example, mutations affecting
phototransduction genes leading to elevated cGMP is expected to cause toxic Ca2+ influx into the outer segment
via the cGMP-gated channels. Although a reasonable hypothesis, it is difficult to reconcile with 1) the cell death
machinery is localized in the inner segment, and 2) the current dogma that the outer and inner segments Ca2+
are compartmentalized and insulated from each other. This raises an important and unanswered question: how
does [Ca2+] buildup in the outer segment alter [Ca2+] in the inner segment to activate cell death? Our central
hypothesis is that altered Ca2+ homeostasis at the outer segment leads to mitochondrial stress at the inner
segment. This, in turn, allows Ca2+ to equilibrate with the proximal cell compartments where the cell death
machinery resides. To test this hypothesis, we will use mouse models that express genetically encoded,
ratiometric Ca2+ indicators in retinal rods and cones. To prevent activating the photoreceptor cells, we will use 1)
a multiphoton microscope equipped with a super-sensitive HyD detector that images under extremely low photon
flux and 2) mouse models with attenuated phototransduction to reduce Ca2+ feedback. Using retinae obtained
from both male and female mice, we will image [Ca2+]i from different cellular compartments simultaneously, in
both dark adapted and light exposed conditions, in healthy and degenerating photoreceptors, to visualize how
changes in [Ca2+] in one cellular compartment may affect [Ca2+] in another compartment. The proposed
experiments should provide a better understanding of the role of Ca2+ homeostasis in health and disease.

## Key facts

- **NIH application ID:** 10801516
- **Project number:** 2R01EY012155-22
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jeannie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,444
- **Award type:** 2
- **Project period:** 1998-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801516

## Citation

> US National Institutes of Health, RePORTER application 10801516, Phototransduction in health and disease (2R01EY012155-22). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10801516. Licensed CC0.

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