I. Phototransduction mechanisms in rods and cones Vertebrate rod and cone photoreceptors transduce light into electrical signals using a sequence of biochemical reactions that result in high signal amplification and precisely timed negative feedback. Rod photoreceptors are exquisitely sensitive to light and signal the timing and number of small numbers (1-3) of photons to the rest of the visual system with high fidelity. Without phototransduction, an otherwise willing neural circuit is left without input and is rendered useless. We are studying phototransduction, in particular the mechanisms that control the duration of signaling in rods and cones, and how these mechanisms ultimately might limit the sensitivity and temporal resolution of vision in both dim and bright light.
II. In vivo retinal imaging In collaboration with Robert Zawadzki and colleagues, we are using optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO) and adaptive optics imaging methods to monitor photoreceptor degeneration over time and how the degeneration impacts the integrity of other retinal cell types, including retinal microglia and infiltrating macrophages, that are recruited as neurodegeneration proceeds.
III. Inflammation during photoreceptor degeneration Retinal degeneration is the leading cause of blindness and costs society billions of dollars annually in disability and lost productivity, a burden that is predicted to worsen as baby-boomers age. All current treatments for retinal degeneration, including experimental therapeutics like stem cell or gene replacement therapy, are thought to be most effective when degeneration is caught in its earliest stages. Unfortunately, the earliest detectable symptom of degeneration is often visual impairment, which is only detectable after a large number of retinal cells have died and disappeared. The ability to discern the first signs of cell stress, prior to apoptosis and degeneration, could significantly improve the likelihood of delaying or preventing vision loss. One common early indication of pending degeneration is activation of retinal microglia, the resident retinal immune cells, which can proliferate, migrate to and phagocytose injured neurons. Our work seeks to define the earliest changes in microglia during photoreceptor degeneration. Using high-resolution, adaptive optics imaging, we are determining the 3- dimensional morphology and dynamics of individual retinal microglia in vivo, and investigating the mechanisms that control their number, distribution and morphology. We are also determining the time course by which circulating macrophages infiltrate the outer retina, and evaluating the degree to which both of these cell types promote or undermine photoreceptor survival. This work will contribute to our long-term goal to monitor and manipulate microglial dynamics in vivo so as to provide earlier detection of and assessment of treatments for retinal degenerative disease.