STRA6 and Ocular Vitamin A Homeostasis

STRA6 和眼部维生素 A 稳态

• 批准号: 10468318
• 负责人: Johannes Friedrich von Lintig
• 金额: $ 46.95万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468318
• 关键词: Adult; Albumins; All-Trans-Retinol; Animal Model; Animals; Area; Biochemical; Biochemistry; Biology; Blood; Blood capillaries; Cell Culture Techniques; Cell Differentiation process; Characteristics; Chronic Disease; Chylomicrons; Control Animal; Data; Dependence; Diabetes Mellitus; Diabetic Retinopathy; Diet; Dietary Intervention; Disease; Disease Progression; Esters; Etiology; Eye; Fat-Soluble Vitamin; Foundations; Generations; Genetic; Goals; Health; Hepatic; Hereditary Disease; High Pressure Liquid Chromatography; Homeostasis; Imaging Techniques; Immunity; Impairment; Knockout Mice; Knowledge; Laboratories; Measurement; Measures; Membrane Proteins; Metabolic Control; Metabolism; Methodology; Modeling; Molecular; Mus; Ocular Pathology; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmacology; Phenotype; Photoreceptors; Physiological; Physiology; Positioning Attribute; Process; Property; RBP4 gene; Reagent; Research; Research Design; Retina; Retinal Pigments; Retinoids; Retinol Binding Proteins; Role; Side; Signal Transduction; Structure of retinal pigment epithelium; Techniques; Testing; Therapeutic Intervention; Tissues; Tretinoin; Vision; Vitamin A; Vitamin Deficiency; diabetic; dietary; inflammatory marker; insight; lipoprotein lipase; mouse model; non-diabetic; novel; protein biomarkers; protein expression; receptor; response; therapeutic development; tool; transcriptome; uptake

ABSTRACT The fat soluble vitamin A (all-trans-retinol) must be distributed in the body to maintain retinoid signaling in the periphery and vision in the eyes. This transport occurs via two overlapping pathways: vitamin A from the diet is distributed in the form of retinyl esters in chylomicrons and vitamin A from hepatic stores is distributed bound to the retinol binding protein RBP4 (holo- RBP4). Cellular uptake of vitamin A from these two transport modes is facilitated by lipoprotein lipase and by the RBP4 receptor STRA6 (stimulated by retinoic acid 6), respectively. Deficiency of vitamin A transport is a serious health problem and associated with blinding diseases. We have generated a STRA6-deficient mouse model. As demonstrated by our recent studies and preliminary data, ocular retinoid concentrations can be manipulated in this mouse model in by dietary intervention. Control mice can maintain their ocular retinoids under this condition. Thus, this mouse model presents a unique animal model to study the biochemistry of vitamin A and physiology of transport and the consequences of its pathological impairment in certain disease states. In Aim 1 we will analyze the role of the RBP4 receptor in leveling ocular vitamin A as a bidirectional transporter in live animals. In Aim 2, we will use the Stra6 knockout mouse to analyze the consequences of imbalances in ocular retinoid concentrations for ocular health. By combining the knowledge of aberrant genetic pathways with imaging techniques and biochemical analyses, we will connect the transcriptome to the phenotype of the eyes in the vitamin A deficient and sufficient states. In Aim 3 we will study whether disturbances in ocular vitamin A metabolism is a characteristic of the etiology of diabetic retinopathy and will test whether reduced ocular vitamin A concentration can alleviate pathological consequences of this disease in the mouse eyes. Collectively, our proposed studies will advance our current knowledge about the biology of ocular vitamin A homeostasis. Our studies will describe the molecular and biochemical framework through which ocular vitamin A homeostasis is maintained in the physiological state and decipher the pathological consequences of perturbed ocular vitamin A import and export in disease states.

抽象的 脂溶性维生素A（全反式视黄醇）必须在体内分布以维持类视黄醇 周围的信号和眼睛的视觉。这种传输通过两个重叠的 途径：饮食中的维生素 A 以视黄酯的形式分布在乳糜微粒中 肝脏储存的维生素 A 与视黄醇结合蛋白 RBP4（holo- RBP4)。脂蛋白促进细胞从这两种运输方式摄取维生素 A 脂肪酶和 RBP4 受体 STRA6（受视黄酸 6 刺激）分别。不足 维生素 A 运输的障碍是一个严重的健康问题，并与致盲疾病有关。我们 已经生成了 STRA6 缺陷小鼠模型。正如我们最近的研究所证明的那样 初步数据显示，可以通过以下方式在该小鼠模型中操纵眼部视黄醇浓度： 饮食干预。对照小鼠在此条件下可以维持其眼部视黄醇。因此， 该小鼠模型提供了一种独特的动物模型来研究维生素 A 和 运输生理学及其在某些疾病中病理损伤的后果 州。 在目标 1 中，我们将分析 RBP4 受体在平衡眼部维生素 A 中的作用 活体动物中的双向转运蛋白。在目标 2 中，我们将使用 Stra6 基因敲除小鼠 分析眼部视黄醇浓度不平衡对眼部健康的影响。经过 将异常遗传途径的知识与成像技术相结合 生化分析，我们将把转录组与眼睛的表型联系起来 维生素A缺乏和充足状态。在目标 3 中，我们将研究眼部是否受到干扰 维生素 A 代谢是糖尿病视网膜病变病因学的一个特征，将测试 降低眼部维生素A浓度是否可以减轻这种病理后果 小鼠眼睛疾病。总的来说，我们提出的研究将推进我们目前的研究 有关眼部维生素 A 稳态的生物学知识。我们的研究将描述 眼部维生素 A 稳态的分子和生化框架 维持生理状态并破译扰动的病理后果 疾病状态下眼部维生素 A 的导入和导出。