STRA6 and Ocular Vitamin A Homeostasis

STRA6 和眼部维生素 A 稳态

• 批准号: 10238900
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238900
• 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.

摘要 脂溶性维生素A（全反式视黄醇）必须在体内分布，以维持类维生素A 周边的信号和眼睛的视觉。这种运输是通过两个重叠的 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， 来自肝脏储存的维生素A与视黄醇结合蛋白RBP 4（holo- RBP4）。脂蛋白促进细胞从这两种转运方式摄取维生素A 脂肪酶和RBP 4受体STRA 6（由视黄酸6刺激）。缺乏 维生素A运输的障碍是一个严重的健康问题，并与致盲性疾病有关。我们 已经建立了一个STRA 6缺陷的小鼠模型。正如我们最近的研究所表明的那样， 初步数据显示，在该小鼠模型中， 饮食干预对照小鼠在这种条件下可以维持其眼部类维生素A。因此，在本发明中， 该小鼠模型提供了研究维生素A的生物化学的独特动物模型， 运输生理学及其在某些疾病中病理损害的后果 states. 在目标1中，我们将分析RBP 4受体在眼维生素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Stra 6敲除小鼠， 分析眼部维甲酸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， 通过生物化学分析，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，我们将研究眼内干扰是否 维生素A代谢是糖尿病视网膜病变的病因学特征， 降低眼部维生素A浓度是否可以减轻这种疾病的病理后果 老鼠眼中的疾病总的来说，我们提出的研究将推动我们目前的 关于眼部维生素A体内平衡的生物学知识。我们的研究将描述 分子和生物化学框架，通过它眼维生素A稳态是 维持在生理状态和破译的病理后果扰乱 眼维生素A的进口和出口疾病状态。