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 regulates circadian physiology in the retina. Together with dopamine, melatonin plays a pivotal role in the modulation of visual sensitivity and adaptation by photoperiod and circadian clocks. Melatonin also protects retinal cells from oxidative damage. Our long-term goal is to understand the control of retinal circadian clocks and their output signals - NAS, metatonin and dopamine. In this application, we propose to test the hypotheses that a light-evoked surge in dopamine release at dawn resets and synchronizes the circadian clocks throughout the retina, serving as a master regulator of circadian physiology, and that a clock generated rhythm of a transcription factor, NPAS2, serves as an output signal to generate the rhythms of cAMP, NAS, and melatonin synthesis. These studies will be conducted using an integrated research approach involving biochemical, pharmacological, genetic, and cellular/molecular biological methodologies. The research is significant because it characterizes cellular and biochemical systems that play an important role in the regulation of retinal physiology and photoreceptor cell function. It is anticipated that characterization of these systems will contribute to the understanding of visual cell physiology and some of the pathological processes that underlie photoreceptor degeneration. Circadian function and the synthesis of NAS and melatonin synthesis decline with age, and disruption of circadian clock genes can cause premature aging and age-related pathologies. Melatonin and NAS decrease oxidative damage. Damage due to oxidative stress may contribute to the development of age- related macular degeneration (AMD), the major cause of blindness in people over 50. This research investigates the circadian control of NAS and melatonin synthesis in photoreceptors, as well as the control of circadian clock networks throughout the retina, which may lead to novel, rationale strategies to prevent AMD and other age-related ocular pathologies.
Showing the most recent 10 out of 141 publications
