From left: Michael Iuvone, Rashidul Haque, Li He, April Masters, Julien Brock, Susov Dhakal, Leela Sankaran, Polina Lyuboslavsky and Micha Chrenek in Dr. Iuvone's Emory Eye Center laboratory.
P Michael Iuvone, PhD, Director (EEC, EUSOM)
Iuvone Core Lab Team, Emory Eye Center
Brock, Julien, Research Specialist
Chrenek, Micah, BS, Lab Manager
Dhakal, Susov, PhD, Post-Doctoral Fellow
Haque, Rashidul, PhD, Research Specialist
He, Li, PhD, Post-Doctoral Fellow
Lyuboslavsky, Polina, Research Specialist
Masters, April Brooke, Research Specialist
Zhang, Shuo, Visiting Scholar
Circadian Rhythms in Retina: Function and Regulation
Circadian clocks generate daily biological rhythms that provide adaptive advantage to organisms by allowing them to anticipate and prepare for regular daily changes in their environment, such as changes of light intensity between day and night. Melatonin and N-acetylserotonin (NAS) are circadian modulators synthesized in retina, primarily in photoreceptor cells. Circadian rhythms of NAS and melatonin synthesis, with peak levels at night, are directly controlled by clocks located in retinal cells.
Melatonin affects cellular functions of photoreceptors, pigment epithelial cells, and dopamine neurons, and optimizes retinal physiology for nighttime, scotopic vision. Melatonin also protects retinal cells from oxidative damage and age-related neuronal cell death. Together with dopamine, melatonin plays a pivotal role in the modulation of visual sensitivity and adaptation by photoperiod and circadian clocks.
Dopamine also regulates multiple aspects of retinal function, optimizing retinal circuitry for daytime, photopic vision. Many aspects of photopic vision are regulated by circadian clocks, in particular contrast sensitivity and photopic ERG response, and these are modulated by dopamine by controlling the expression of circadian clock genes and clock-controlled genes. Circadian clocks also regulate the sensitivity to light-induced photoreceptor degeneration, as well as vision-guided refractive development and myopia. Compromised circadian function and reduced dopamine have been implicated in visual dysfunction in early diabetes and in other retinal disorders.
Our long-term goal is to understand organization of retinal circadian clock networks and their impact on visual function and dysfunction. Our research in this area is significant because it characterizes cellular and biochemical systems that play an important role in the regulation of retinal physiology and photoreceptor cell function and viability.
Characterization of these systems is contributing to the understanding of visual cell physiology and some of the pathological processes that underlie diabetic retinopathy, photoreceptor dystrophies, and age-related retinal dysfunction.
Development of small molecule agonists of TrkB receptors for treatment of retinal degenerative diseases and trauma-induced eye and brain injury
TrkB is the cognate receptor for Brain-Derived Neurotrophic Factor (BDNF). BDNF and TrkB play important roles in neurogenesis, neuronal development, and synaptic plasticity. BDNF is protective in several models of neurodegeneration (e.g., Parkinson disease and Alzheimer disease). BDNF and TrkB activating antibodies have been shown to be protective in models of photoreceptor degeneration and glaucoma. BDNF is a relatively large protein that does not cross the blood brain barrier when administered systemically, thus limiting its therapeutic utility.
Our recent finding that N-acetylserotonin (NAS) binds to and activates TrkB (Jang et al., PNAS 2010) indicates that small molecules that cross the blood brain barrier can mimic the effect of BDNF. We are developing a new class of TrkB receptor agonist whose members are protective in models of neurodegeneration (Shen et al., PNAS 2012).
These NAS derivatives bind TrkB receptors with high affinity, induce their dimerization and autophosphorylation, and activate downstream signaling. Their effects are obtained with local or systemic delivery. These drugs reduce light-induced photoreceptor degeneration, and also slow or prevent vision loss following blast-induced traumatic brain or eye injury.
We anticipate that these drugs will be useful for the treatment of retinal diseases, such as retinitis pigmentosa, age-related macular degeneration, and glaucoma, and for trauma-induced eye and brain injury, as well as depression and neurodegenerative diseases affecting the brain.