Mechanisms of vitamin A deprivation and replacement therapy

项目总结/摘要 维生素A对人类健康和视力至关重要。维生素A摄入不足会严重损害 光感受器，导致视觉色素的损失，并且是可预防的 儿童失明，根据WHO。然而，很少有人知道维生素A 剥夺在分子水平上影响光感受器，以及维生素A替代疗法如何 介导结构和功能性光感受器恢复。我们的长期目标是利用 果蝇视网膜作为一个模型，以填补这一空白，在我们的知识和分析 基本机制。 这项建议协同结合果蝇遗传学，免疫组织化学，行为， 分析和定量蛋白质组学这种多学科的方法将使我们能够评估 中心假设，不同的感光器类型-功能等同于人类杆 和视锥细胞-对维生素A缺乏的反应不同，维生素A缺乏会引发 稳定受损感光细胞的保护机制。我们将追求三大目标 具体目标。首先，我们将分析不同类型的感光细胞如何对维生素A做出反应 剥夺其次，我们试图确定蛋白质和细胞通路， 维生素A缺乏和维生素A替代疗法。第三，我们将确定 一种新的跨膜蛋白，我们发现它在缺乏维生素A的小鼠中高度上调， 视网膜来稳定受损的光感受器。 拟议的研究是重要的，因为它将为分子生物学提供基本见解。 不同类型的感光细胞对维生素A缺乏的反应。它还将揭示维生素 替代疗法导致光感受器结构和功能的改善。总的来说， 这一建议有可能确定稳定受损光感受器的机制， 为治疗人类眼疾开辟新的途径。

Project Summary/Abstract Vitamin A is critical for human health and vision. Insufficient uptake of vitamin A severely damages photoreceptors, causes a loss of visual pigments, and is the leading cause of preventable childhood blindness according to the WHO. However, little is known about how vitamin A deprivation affects photoreceptors on the molecular level and how vitamin A replacement therapy mediates structural and functional photoreceptor recovery. Our long-term goal is to use the Drosophila melanogaster retina as a model to fill this gap in our knowledge and to analyze the underlying mechanisms. This proposal synergistically combines Drosophila genetics, immunohistochemistry, behavioral analysis, and quantitative proteomics. This multidisciplinary approach will allow us to evaluate the central hypotheses that different photoreceptor types – functionally equivalent to human rods and cones - respond differently to vitamin A deprivation and that vitamin A deficiency triggers protective mechanisms that stabilize damaged photoreceptors. We will pursue three major specific aims. First, we will analyze how different photoreceptor types respond to vitamin A deprivation. Second, we seek to identify the proteins and cellular pathways that are affected by vitamin A deprivation and vitamin A replacement therapy. Third, we will determine the function of a novel transmembrane protein that we found to be highly upregulated in vitamin A-deprived retinas to stabilize the damaged photoreceptors. The proposed research is significant, as it will provide fundamental insights into the molecular response of different photoreceptor types to vitamin A deprivation. It will also unravel how vitamin A replacement therapy leads to improvement of photoreceptor structure and function. Collectively, this proposal has the potential to identify mechanisms that stabilize damaged photoreceptors and to open new avenues for treating human eye diseases.