Mechanisms of vitamin A deprivation and replacement therapy

维生素 A 剥夺和替代疗法的机制

• 批准号: 10327315
• 负责人: Jens Rister
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327315
• 关键词: Address; Affect; Antibodies; Behavioral; Biosensor; Blindness; Childhood; Color; Cone; Cytoplasm; Defect; Drosophila genus; Drosophila melanogaster; Event; Eye diseases; Genetic; Glutathione; Glutathione Disulfide; Goals; Health; Homeostasis; Human; Immunohistochemistry; Integral Membrane Protein; Knowledge; Light; Mediating; Methods; Modeling; Molecular; Morphology; Natural regeneration; Oxidation-Reduction; Pathway interactions; Photoreceptors; Pigments; Proteins; Proteome; Proteomics; Recovery; Replacement Therapy; Research; Retina; Retinal Diseases; Retinal Pigments; Rhodopsin; Rod; Role; Structure; Testing; Vertebrate Photoreceptors; Vision; Vitamin A; Vitamin A Deficiency; World Health Organization; deprivation; dietary manipulation; in vivo; insight; interdisciplinary approach; novel; novel strategies; photoreceptor degeneration; preservation; response; uptake

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.

项目概要/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，导致视觉色素损失，是可预防的主要原因 根据世界卫生组织的数据，人们对维生素 A 的作用知之甚少。 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 我们的长期目标是利用光感受器的结构和功能恢复。 果蝇视网膜作为模型来填补我们的知识空白并分析 底层机制。 该提案协同结合了果蝇遗传学、免疫组织化学、行为学 这种多学科方法将使我们能够评估 中心假设是不同的光感受器类型——功能上与人类视杆细胞相同 和视锥细胞 - 对维生素 A 缺乏和维生素 A 缺乏引发的反应不同 我们将追求三个主要的保护机制。 首先，我们将分析不同类型的光感受器对维生素 A 的反应。 其次，我们试图找出受剥夺影响的蛋白质和细胞途径。 维生素A剥夺和维生素A替代疗法第三，我们将确定维生素A的功能。 我们发现一种新型跨膜蛋白在缺乏维生素 A 的情况下高度上调 视网膜以稳定受损的感光器。 拟议的研究意义重大，因为它将提供分子生物学的基本见解 不同光感受器类型对维生素 A 缺乏的反应也将揭示维生素 A 的作用。 总的来说，替代疗法可以改善光感受器的结构和功能。 该提议有可能确定稳定受损感光器的机制 为治疗人类眼部疾病开辟新途径。