STRA6 and Ocular Vitamin A Homeostasis

STRA6 和眼部维生素 A 稳态

基本信息

批准号：
9751863
负责人：
Johannes Friedrich von Lintig
金额：
$ 48.13万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9751863
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 Pigment Epithelium Positioning Attribute Process Property RBP4 gene Reagent Research Research Design Retina Retinal Retinal Pigments Retinoids Retinol Binding Proteins Role Side Signal Transduction 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

项目摘要

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（全反元素）必须分布在体内以维持类维生素在眼睛的外围和视力中发出信号。这种运输是通过两个重叠发生的途径：饮食中的维生素A以乳糜微粒的视黄酯的形式分布来自肝储存的维生素A分布与视黄醇结合蛋白RBP4结合（Holo-- RBP4）。脂蛋白促进了这两种传输模式的维生素A的细胞摄取脂肪酶和RBP4受体Stra6（由视黄酸6刺激）。不足维生素A运输是一个严重的健康问题，与盲目疾病有关。我们已经生成了Stra6缺陷鼠标模型。正如我们最近的研究所证明的那样初步数据，可以在此鼠标模型中操纵眼类维生素的浓度饮食干预。对照小鼠可以在这种情况下维持其眼类视黄素。因此，该小鼠模型提出了一种独特的动物模型，用于研究维生素A的生物化学和运输生理学及其在某些疾病中的病理障碍的后果国家。在AIM 1中，我们将分析RBP4受体在将眼维生素A升级为A中的作用活动物中的双向转运蛋白。在AIM 2中，我们将使用Stra6敲除鼠标分析眼类维生素浓度失衡对眼部健康的后果。经过将异常遗传途径的知识与成像技术相结合，生化分析，我们将将转录组连接到眼睛的表型维生素一种不足和足够的状态。在AIM 3中，我们将研究眼中的干扰维生素A代谢是糖尿病性视网膜病的病因的特征，将测试降低眼维生素A浓度是否可以减轻这种情况的病理后果小鼠眼睛中的疾病。总的来说，我们提出的研究将推动我们的当前关于眼维生素A稳态的生物学的知识。我们的研究将描述眼部维生素A稳态的分子和生化框架是保持在生理状态并破译扰动的病理后果眼维生素是疾病状态的进出口。