Ocular Diurnal Rhythms and Eye Growth

描述（由申请人提供）：在美国，近视影响了近25%的人口，而在某些其他发达国家，受近视影响的人口比例增加到80%甚至更多。病理性近视也是失明的主要原因。因此，了解眼部生长调控的机制对于理解眼睛如何以及为什么会发生屈光不正至关重要。我的大部分工作都是研究眼部昼夜节律对眼睛生长调节的影响。了解这些影响可能会导致时间依赖疗法（时间疗法）的发展，就像其他病理（包括癌症）一样。在之前的资助期间，我已经确定在脉络膜厚度的增加和眼伸长的抑制之间存在紧密的联系。此外，我们发现气态递质一氧化氮（NO）可能影响脉络膜厚度的变化，进而影响眼部生长。一氧化氮是由脉络膜产生的，从药理学上抑制其合成可防止脉络膜和生长对离焦的反应。脉络膜NO在体外也显示出昼夜节律。我现在建议研究脉络膜在眼睛生长的视觉调节中的具体作用。我建议研究三种信号分子——一氧化氮（NO）、多巴胺和乙酰胆碱（ACh）——与脉络膜增厚和眼睛生长的关系。多巴胺和乙酰胆碱是否都影响一氧化氮和/或脉络膜厚度？NO是脉络膜反应的中介还是独立的？在信号级联中，这些分子在哪里发挥作用？最后，我之前已经发现眼伸长的昼夜节律与脉络膜厚度的昼夜节律之间的相位差与脉络膜厚度和眼长的变化都相关。我现在要问的是，这个相位差对于透镜补偿，以及一般意义上的平面化是否必要。这些目的的结果将使我们更接近于理解信号级联介导的眼部生长变化。目的1：确定副交感神经和交感神经支配脉络膜在脉络膜和生长反应中的作用。目标2。确定多巴胺和乙酰胆碱在脉络膜和生长反应中的作用，以及它们如何影响NO的产生。目标3。区分脉络膜厚度节奏的相位推进和瞬态脉络膜响应的相位依赖。公共卫生相关性：近视在亚洲达到流行病的程度，病理性近视是失明的主要原因。了解环境（视力）如何影响视网膜和巩膜之间的信号级联，从而产生近视，对于开发改善近视的药物疗法至关重要。出于同样的原因，理解眼生理节律在眼睛生长控制中的作用对于确定这些疗法是否依赖于一天中的时间（时间疗法）至关重要，就像在其他病理中发现的那样，包括某些癌症。

DESCRIPTION (provided by applicant): 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.