# Phototransduction in health and disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $412,500

## 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? Currently, direct
evidence for disrupted Ca2+ homeostasis as an instigator of cell death is scarce due to the lack of systematic
physiological imaging of Ca2+ levels in different cellular compartments of healthy and diseased mammalian
photoreceptors. A major technical challenge is that the photons emitted during fluorescent imaging can activate
visual pigments, which, in turn, triggers a rapid feedback in phototransduction to lower [Ca2+]i, making imaging
these light-sensitive cells in their dark-adapted basal state technically difficult. To overcome this challenge, 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. Our central hypothesis is that altered Ca2+ homeostasis
in the dark state and impaired Ca2+ dynamics during light exposure is a primary driver of cell death in certain
mutations affecting the phototransduction cascade. The proposed experiments should provide a better
understanding of the role of Ca2+ homeostasis in health and disease.

## Key facts

- **NIH application ID:** 10440206
- **Project number:** 2R01EY012155-21A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jeannie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,500
- **Award type:** 2
- **Project period:** 1998-03-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440206

## Citation

> US National Institutes of Health, RePORTER application 10440206, Phototransduction in health and disease (2R01EY012155-21A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10440206. Licensed CC0.

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