Ocular Diurnal Rhythms and Eye Growth

描述(申请人提供)：在美国，近视影响近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%或更多。病理性近视也是导致失明的主要原因。因此，了解眼睛生长调节的机制对于了解屈光不正的眼睛是如何以及为什么会出现问题至关重要。我的大部分工作都研究了眼睛昼夜节律在眼睛生长调节中的影响。了解这些影响可能会导致依赖时间的治疗方法的发展(计时疗法)，就像对包括癌症在内的其他病理疾病所发现的那样。在之前的授权期内，我已经证实了脉络膜厚度的增加和眼球延长的抑制之间存在密切的联系。此外，我们发现气体递质一氧化氮(NO)可能影响脉络膜厚度的变化，而脉络膜厚度的变化又可能影响眼睛的生长。NO是由脉络膜产生的，抑制其合成从药物上阻止了脉络膜对离焦的反应和生长反应。体外脉络膜NO也表现出昼夜节律。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)--与脉络膜增厚和眼部生长的关系。多巴胺和ACh对NO和/或脉络膜厚度有影响吗？NO是脉络膜反应的中介物还是独立于它？那么，这些分子在信号级联的哪个环节发挥作用呢？最后，我以前发现，眼球伸长和脉络膜厚度的昼夜节律之间的相位差异与脉络膜厚度和眼长的变化都相关。我现在要问的是，这种相位差对于透镜补偿，也就是说，对于正视化来说，是否是必不可少的。这些目标的结果将使我们更接近于理解调节眼球生长变化的信号级联。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。目的2.确定多巴胺和乙酰胆碱在脉络膜反应和生长反应中的作用以及它们如何影响一氧化氮的产生。目的3.区分脉络膜厚度节律中的相位提前和正视术中瞬时脉络膜反应的相位依赖性。公共卫生相关性：近视在亚洲正达到流行的比例，病理性近视是导致失明的主要原因。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。同样，了解眼睛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像在其他病理学中发现的那样依赖于一天中的时间(时间疗法)至关重要，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.