STRA6 and Ocular Vitamin A Homeostasis

STRA6 和眼部维生素 A 稳态

• 批准号: 9982937
• 负责人: Johannes Friedrich von Lintig
• 金额: $ 48.4万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982937
• 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; 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.

摘要 脂溶维生素A(全反式视黄醇)必须分布在体内以维持视黄醇 在周围发出信号，在眼睛里发出视觉信号。这种传输通过两个重叠的 途径：饮食中的维生素A以视黄酸酯的形式分布在乳糜粒和 来自肝脏的维生素A分布与视黄醇结合蛋白RBP4(全息)结合。 RBP4)。脂蛋白促进细胞从这两种转运途径摄取维生素A 脂肪酶和RBP4受体STRA6(由维甲酸6刺激)。缺憾 维生素A运输障碍是一个严重的健康问题，并与致盲疾病有关。我们 已经产生了一种STRA6缺陷的小鼠模型。正如我们最近的研究和 初步数据显示，在这个小鼠模型中，眼部维甲酸浓度可以通过 饮食干预。在这种情况下，对照组小鼠可以保持其眼部视黄醇。因此， 该小鼠模型为研究维生素A和维生素A的生物化学提供了一种独特的动物模型 某些疾病的运输生理学及其病理损害的后果 各州。 在目标1中，我们将分析RBP4受体在调节眼睛维生素A水平中的作用。 活体动物的双向转运蛋白。在目标2中，我们将使用Stra6基因敲除鼠标来 分析眼部视黄醇浓度失衡对眼部健康的影响。通过 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缺乏和充足的状态。在目标3中，我们将研究眼球运动障碍 维生素A代谢是糖尿病视网膜病变病因学的一个特征，并将测试 降低眼部维生素A浓度是否可以减轻这种情况的病理后果 老鼠眼睛里的疾病。总体而言，我们提议的研究将推进我们目前的 眼部维生素A动态平衡生物学知识。我们的研究将描述 眼部维生素A稳态的分子和生化框架 维持在生理状态并破译心烦意乱的病理后果 眼部维生素A在疾病状态下的进出口。