In the United States, myopia affects nearly 25% of the population, while in certain other developed countries the proportion of the population affected increases to 80% or more. Pathological myopia is also a leading cause of blindness. Therefore, understanding the mechanisms underlying the regulation of ocular growth is critical towards understanding how and why it goes awry in eyes that develop ametropias. Much of my work has examined the influence of ocular circadian rhythms in eye growth regulation. Understanding these influences might lead to the development of therapies that are time-dependent (chronotherapies), as has been found for other pathologies, including cancer. During the previous grant period, I have established that there is a tight link between increases in choroidal thickness and inhibition of ocular elongation. Furthermore, we found that the gaseous transmitter nitric oxide (NO) might influence the changes in choroidal thickness that in turn may influence ocular growth. NO is produced by the choroid, and inhibiting its synthesis pharmacologically prevents both the choroidal and growth responses to defocus. Choroidal NO also shows a circadian rhythm in vitro. I now propose to examine the specific role of the choroid in the visual regulation of eye growth. I propose to study three signal molecules--nitric oxide (NO), dopamine, and acetylcholine (ACh)-in relation to choroidal thickening and ocular growth. Do both dopamine and ACh influence NO and/or choroidal thickness? Is NO the mediator of the choroidal response or independent of it? And, where in the signal cascade do these molecules exert their effect? Finally, I have previously found that the phase difference between the circadian rhythm of ocular elongation and that of choroidal thickness is correlated with both the changes in choroidal thickness and ocular length. I now ask whether this phase difference is essential for lens-compensation, and, by implication, for emmetropization in general. The results from these Aims will bring us closer to understanding the signal cascade mediating changes in ocular growth.
Aim 1 : To determine the role of the parasympathetic and sympathetic innervation to the choroid in the choroidal and growth response.
Aim 2. To determine the roles of dopamine and acetylcholine in the choroidal and growth responses and how they may influence NO production.
Aim 3. To distinguish between the phase advance in the choroidal thickness rhythm and a phase-dependence of the transient choroidal responses in emmetropization.

Public Health Relevance

Myopia is reaching epidemic proportions in Asia and pathological myopia is a leading cause of blindness. Understanding how the environment (vision) influences the signal cascade between retina and sclera to produce myopia is crucial to developing drug therapies that will ameliorate it. By the same token, understanding the roles of ocular physiological rhythms in eye growth control is crucial to determining whether these therapies might depend on time of day (chronotherapy), as has been found in other pathologies, including certain cancers.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013636-08
Application #
8238361
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (92))
Program Officer
Wiggs, Cheri
Project Start
2001-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$252,048
Indirect Cost
$85,728
Name
New England College of Optometry
Department
Other Basic Sciences
Type
Schools of Optometry/Ophthalmol
DUNS #
076614874
City
Boston
State
MA
Country
United States
Zip Code
02115
Nickla, Debora L (2013) Ocular diurnal rhythms and eye growth regulation: where we are 50 years after Lauber. Exp Eye Res 114:25-34
Morgan, Ian G; Ashby, Regan S; Nickla, Debora L (2013) Form deprivation and lens-induced myopia: are they different? Ophthalmic Physiol Opt 33:355-61
Nickla, Debora L; Zhu, Xiaoying; Wallman, Josh (2013) Effects of muscarinic agents on chick choroids in intact eyes and eyecups: evidence for a muscarinic mechanism in choroidal thinning. Ophthalmic Physiol Opt 33:245-56
Nickla, Debora L; Totonelly, Kristen (2011) Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia. Exp Eye Res 93:782-5
Stubinger, Karin; Brehmer, Axel; Neuhuber, Winfried L et al. (2010) Intrinsic choroidal neurons in the chicken eye: chemical coding and synaptic input. Histochem Cell Biol 134:145-57
Nickla, Debora L; Wallman, Josh (2010) The multifunctional choroid. Prog Retin Eye Res 29:144-68
Nickla, Debora L; Totonelly, Kristen; Dhillon, Balprit (2010) Dopaminergic agonists that result in ocular growth inhibition also elicit transient increases in choroidal thickness in chicks. Exp Eye Res 91:715-20
Nickla, Debora L; Damyanova, Petya; Lytle, Grace (2009) Inhibiting the neuronal isoform of nitric oxide synthase has similar effects on the compensatory choroidal and axial responses to myopic defocus in chicks as does the non-specific inhibitor L-NAME. Exp Eye Res 88:1092-9
Kee, Chea-Su; Deng, Li (2008) Astigmatism associated with experimentally induced myopia or hyperopia in chickens. Invest Ophthalmol Vis Sci 49:858-67
Schrodl, Falk; Brehmer, Axel; Neuhuber, Winfried L et al. (2006) The autonomic facial nerve pathway in birds: a tracing study in chickens. Invest Ophthalmol Vis Sci 47:3225-33

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