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.

项目摘要/摘要 维生素A对于人类健康和视力至关重要。维生素的摄取不足严重损害 感光器会导致视觉颜料损失，是可预防的主要原因 根据世卫组织的童年失明。但是，关于维生素A的了解知之甚少 剥夺会影响分子水平上的光感受器以及维生素A替代疗法 介导结构和功能感受器恢复。我们的长期目标是使用 果蝇Melanogaster视网膜作为填补这一空白的模型，并分析 基本机制。 该建议协同结合了果蝇遗传学，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 中心假设是不同的光感受器类型 - 在功能上等同于人棒 和锥 - 对维生素A剥夺的反应不同，维生素A缺乏症会触发 稳定受损的光感受器的保护机制。我们将追求三个主要 具体目标。首先，我们将分析不同的光感受器类型对维生素A的反应 剥夺。其次，我们试图确定受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 一种新型的跨膜蛋白 视网膜稳定受损的光感受器。 拟议的研究很重要，因为它将为分子提供基本见解 不同感受器类型对维生素A剥夺的反应。它也将解散维生素 替代疗法可改善感光体的结构和功能。共同 该提案有潜力确定稳定受损的感光器和的机制 为治疗人眼疾病的新途径开放。