Understanding the mechanisms that maintain photoreceptor health and survival is critical, since there is no treatment to reverse photoreceptor death associated with ocular diseases such as Macular Degeneration (MD), the leading cause of vision impairment and blindness. This devastating disease is often specifically associated with the death of cone photoreceptors, which are highly concentrated in the macula. The circadian time-keeping mechanism in photoreceptors is known to regulate its function and physiology, and disruption of photoreceptor circadian rhythms leads to photoreceptor death. However, it is still not completely understood how photoreceptor circadian rhythms are regulated, and why photoreceptors are more sensitive to light damage at night. Hence, there is a critical need to understand the cellular mechanisms responsible for cone photoreceptor circadian rhythms, which will uncover key elements leading to the prevention of photoreceptor death and MD. The central hypothesis of this proposal is that protein kinase B (Akt)-related signaling is the major pathway that regulates the circadian rhythm of photoreceptor L-VGCCs, and intense light stimulation at night causes drastic changes of Akt- dependent signaling and L-VGCCs that subsequently triggers photoreceptor apoptosis. Photoreceptor L-VGCCs are essential in gating neurotransmitter release, and the calcium (Ca2+) influx through L-VGCCs triggers subsequent Ca2+- dependent events and affects intracellular Ca2+ homeostasis. Imbalanced intracellular Ca2+ homeostasis is known to trigger cell apoptosis. Hence, precise regulation of L-VGCCs is critical for photoreceptor survival and health. The long-term goals of this research are to understand the molecular mechanisms responsible for the photoreceptor circadian rhythm, and how this rhythm impacts its survival and health. The objectives of this project are to elucidate how microRNAs (miRNAs) integrate into Akt signaling to regulate the circadian rhythm of photoreceptor L-VGCCs and to reveal the functional significance of L-VGCC circadian rhythms especially in intracellular Ca2+ homeostasis. Combinations of bioinformatics analysis, electrophysiology, molecular / biochemical assays, and advanced high resolution microscopy will be used to investigate the following specific aims.
Aim 1. Elucidate how miRNAs regulate the circadian rhythms of photoreceptor L-VGCCs.
Aim 2. Investigate how bright light at night causes photoreceptor apoptosis more severely than during the day.
Aim 3. Determine how the dynamic trio - L-VGCC, retinoschisin (rs1), and plasma membrane Ca2+-ATPase (PMCA1) - promote membrane retention of L-VGCCs and Ca2+ homeostasis. There are physical interactions between L-VGCCs, retinoschisin, and PMCA1, but the functions of these interactions are not clear. The outcomes of these studies will reveal new mechanisms on miRNAs and integrated Akt-related signaling in the regulation of ion channels and circadian rhythms, and how circadian regulation of photoreceptor L- VGCCs contribute to Ca2+ homeostasis, cell survival, and photosensitivity. Understanding the novel functions of miRNAs and integrated signaling pathways will ultimately provide new knowledge for preventing blindness caused by photoreceptor death.

Public Health Relevance

The outcome of the proposed research will reveal new mechanisms that are critical in maintaining retinal photoreceptor health and survival. The proposed research is relevant to public health because understanding the cellular mechanisms of circadian regulation in retinal photoreceptors will ultimately provide knowledge for developing new strategies to treat ocular diseases and especially for preventing blindness caused by macular degeneration, since disruption of circadian rhythms in the retina causes photoreceptor death that could lead to macular degeneration. Therefore, the research proposed in this application is pertinent to part of the mission of the National Eye Institute at NIH in garnering fundamental knowledge that will help promote the prevention and treatment of ocular diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Neuhold, Lisa
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Texas Agrilife Research
Veterinary Sciences
Schools of Veterinary Medicine
College Station
United States
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Shi, Liheng; Ko, Michael L; Huang, Cathy Chia-Yu et al. (2014) Chicken embryos as a potential new model for early onset type I diabetes. J Diabetes Res 2014:354094
Huang, Cathy Chia-Yu; Ko, Michael Lee; Ko, Gladys Yi-Ping (2013) A new functional role for mechanistic/mammalian target of rapamycin complex 1 (mTORC1) in the circadian regulation of L-type voltage-gated calcium channels in avian cone photoreceptors. PLoS One 8:e73315
Ko, Michael L; Shi, Liheng; Huang, Cathy C-Y et al. (2013) Circadian phase-dependent effect of nitric oxide on L-type voltage-gated calcium channels in avian cone photoreceptors. J Neurochem 127:314-28
Huang, Cathy Chia-Yu; Ko, Michael L; Vernikovskaya, Darya I et al. (2012) Calcineurin serves in the circadian output pathway to regulate the daily rhythm of L-type voltage-gated calcium channels in the retina. J Cell Biochem 113:911-22
Ko, Michael L; Shi, Liheng; Tsai, Ju-Yun et al. (2011) Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms. J Biol Rhythms 26:412-22
Ko, Michael L; Jian, Kuihuan; Shi, Liheng et al. (2009) Phosphatidylinositol 3 kinase-Akt signaling serves as a circadian output in the retina. J Neurochem 108:1607-20
Ko, Michael L; Shi, Liheng; Ko, Gladys Y-P (2009) Circadian controls outweigh acute illumination effects on the activity of extracellular signal-regulated kinase (ERK) in the retina. Neurosci Lett 451:74-8
Shi, Liheng; Jian, Kuihuan; Ko, Michael L et al. (2009) Retinoschisin, a new binding partner for L-type voltage-gated calcium channels in the retina. J Biol Chem 284:3966-75
Shi, Liheng; Ko, Michael L; Ko, Gladys Y-P (2009) Rhythmic expression of microRNA-26a regulates the L-type voltage-gated calcium channel alpha1C subunit in chicken cone photoreceptors. J Biol Chem 284:25791-803
Ko, Gladys Y-P; Shi, Liheng; Ko, Michael L (2009) Circadian regulation of ion channels and their functions. J Neurochem 110:1150-69

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