Central Regulation of the Peripheral Visual System

描述（由申请人提供）：每天，我们视网膜中的感光细胞，我们的光感受器，脱落并更新其感光膜的一部分。然而，为什么会发生这个过程尚不完全清楚;它对于人类和动物的健康视力至关重要。事实上，视网膜变性发生在不能脱落感光膜的突变大鼠身上。在大多数动物中，光敏膜的脱落是由生物钟（昼夜节律）调节的，并由生物钟和/或光触发。然而，人们对生物钟和光如何相互作用以触发和调节光敏膜的日常脱落和更新知之甚少。鲎侧眼是研究光感受器膜脱落和更新的重要系统。它的光感受器在许多重要方面与人类的视杆细胞光感受器相似。在目前资助的项目（R15 EY 13196）中，我们开发并测试了光和生物钟在日常瞬态光敏膜脱落调节中相互作用的模型。迄今为止，我们已经了解到，时钟启动视网膜短暂脱落和更新通过cAMP依赖性蛋白激酶（PKA）刺激下调感光蛋白的合成。这个竞争性的延续申请建议通过以下两个具体目标继续评估我们的模型：（1）。调查是否需要下调视觉抑制蛋白的表达，以总理侧眼短暂的横纹肌脱落（TRS），以及是否需要肌动蛋白结合蛋白肌球蛋白III，以稳定对TRS的横纹肌在黎明后的日光。（二）、确定PKA是否通过MAP激酶途径或与之竞争，在TRS的侧眼章鱼胺能引发过程中减少感光蛋白的合成。私家侦探和他的本科生合作者将通过RNA干扰途径使用基因沉默来敲低蛋白质（抑制蛋白和肌球蛋白III）的表达。我们的模型假设，生物钟调节这些蛋白质的表达，可能还有其他蛋白质，通过适当调节光敏膜的日常周转来维持健康的视力。公共卫生意义-使用与人类视网膜有许多相似之处的简单无脊椎动物视网膜对于开发翻译模型至关重要，这些模型可用于推动研究，以防止因日常感光细胞外段更新失败而导致的视网膜变性和失明。让本科生参与生物医学研究对这个国家的能力至关重要，通过招募我们最聪明的年轻公民参与医学和生物医学研究，并培养新一代见多识广的科学教师和大学教授来告知公民。

DESCRIPTION (provided by applicant): Everyday, the light-sensitive cells in our retinas, our photoreceptors, shed and renew a portion of their light-sensitive membrane. Why this process occurs is not completely understood, however; it is essential for healthy vision in humans and animals. In fact, retinal degeneration occurs in mutant rats unable to shed their photosensitive membrane. In most animals, shedding of the photosensitive membrane is regulated by a biological clock (circadian rhythm) and triggered by that clock and/or by light. Relatively little is known, however, about how the biological clock and light interact to trigger and regulate daily shedding and renewal of photosensitive membrane. The lateral eye of the horseshoe crab (Limulus) has long served as an important system for the study of photoreceptor membrane shedding and renewal. Its photoreceptors are similar in many important ways to human rod photoreceptors. In the currently funded project (R15 EY13196), we developed and tested a model for the interaction of light and the biological clock in the regulation of daily transient photosensitive membrane shedding. To date, we have learned that the clock primes the retina for transient shedding and renewal through cAMP-dependent protein kinase (PKA) stimulated downregulation of photoreceptor protein synthesis. This competing continuation application proposes to continue to evaluate our model through the following two specific aims: (1). Investigate whether downregulation of visual arrestin expression is required to prime the lateral eye for transient rhabdom shedding (TRS), and whether the actin-binding protein myosin III is required to stabilize the rhabdom against TRS during post-dawn daylight. (2). Determine whether PKA acts through, or in competition with, a MAP kinase pathway to decrease photoreceptor protein synthesis during octopaminergic priming of the lateral eye for TRS. The P.I. and his undergraduate student collaborators will use gene silencing through the RNA interference pathway to knockdown the expression of proteins (arrestin and myosin III). Our model hypothesizes that the clock regulates the expression of these proteins, and possibly others, to maintain healthy vision through proper regulation of daily turnover of the photosensitive membrane. Public Health Significance - The use of a simple invertebrate retina with many similarities to the human retina is critical to the development of translational models that can be used to drive research to prevent retinal degeneration and blindness caused by failures in daily photoreceptor outer segment turnover. Involving undergraduate students in biomedical research is critical to this Nation's ability advance our public health through recruitment of our brightest young citizens into medicine and biomedical research, and to produce new generations of well-informed science teachers and College professors to inform the Citizenry.