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Molecular Components Affecting Ocular Retinoid Homeostasis

影响眼部视黄醇稳态的分子成分

基本信息

批准号：
8308558
负责人：
Johannes Friedrich von Lintig
金额：
$ 37.3万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308558
关键词：
11 cis Retinal Address Affect All-Trans-Retinol Animal Model Binding Binding Proteins Biochemical Biochemistry Biology Blood Carotene Carotenoids Cell Culture Techniques Cell Differentiation process Cell Line Clinical Data Development Diet Disease Dissection Elements Enzymes Epithelial Eye Eye Development G-Protein-Coupled Receptors Gatekeeping Gene Expression Regulation Genes Genetic Health Homeobox Homeostasis Human Immunity Intestinal Absorption Intestines Knock-out Knockout Mice Knowledge Ligands Lipids Mammals Mediating Membrane Proteins Metabolic Metabolic Control Metabolism Molecular Mouse Strains Mus Mutant Strains Mice Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Oxygenases Pathologic Processes Pathology Pathway interactions Play Prevention Process Production Proteins Receptor Gene Receptor Signaling Regulation Reporter Reporter Genes Research Retinoic Acid Receptor Retinoids Retinol Binding Proteins Role Serum Testing Tissues Tretinoin Vision Visual Vitamin A Vitamins Woods syndrome Work Zebrafish absorption base chromophore embryo tissue human disease improved in vivo insight interest malformation metabolic abnormality assessment mouse model prevent promoter scavenger receptor transcription factor uptake

项目摘要

ABSTRACT The essential role of vitamin A for the vertebrate eye has long been known because deficiency in or excess of this vitamin can impair eye development and function. Vitamin A is the precursor for at least two critical metabolites, 11-cis-retinal, the chromophore of visual G-protein-coupled receptors, and retinoic acid, a ligand for nuclear receptors. Since retinoids cannot be synthesized de novo by humans, dietary precursors must be absorbed by the intestine and metabolically converted. The converted retinoids must then be transported within the body for storage and delivered to target tissues such as the eyes. This process evidently depends on specific transporters and binding proteins. These components have recently attracted broad scientific and clinical interest since they are associated with diseases as diverse as type 2 diabetes and the fatal Matthew- Wood syndrome. Yet our knowledge of the pathology of these diseases is scant due to a lack of studies in homologous mammalian animal models. Such study would contribute to our understanding of the biochemistry of vitamin A transport as well as the regulatory mechanisms that govern retinoid homeostasis. The long-term objective of the proposed studies is to analyze two key steps affecting ocular retinoid metabolism: the intestinal absorption and metabolic conversion of b,b-carotene to retinol and the uptake of b,b-carotene-derived retinol into the eyes. In Aim 1, we will address the role of the intestine specific homeobox transcription factor ISX that suppresses Srb1 and Bcmo1 gene activities which respectively encode a carotenoid transporter and the key enzyme for b,b-carotene conversion into retinoids. By genetic dissection, we will analyze the molecular basis of b,b-carotene absorption and conversion into retinoids and the regulation of this pathway. For this purpose, we will study b,b-carotene metabolism and retinoid homeostasis in Isx, Srb1 and Bcmo1 single and compound knockout mice. Promoter/reporter gene studies will be performed to elucidate the molecular details of this regulation including the role of retinoic acid in this process. In Aim 2, we will establish knockout mice lacking STRA6 (stimulated by retinoic acid 6) protein to study the metabolic basis of the fatal Matthew-Wood syndrome. We also will generate compound knockouts lacking both STRA6 and the serum retinol binding protein 4 (RBP4) to test for the hypothesis that RBP4 triggers the pathological alterations seen in STRA6- deficiency. Furthermore, we will analyze the role retinoic acid in regulating blood retinol homeostasis in the different mouse mutants. These studies will provide new insights into retinoid metabolism and the control of retinoid homeostasis which will improve understanding of human disease states caused by disturbances in this process and may provide concepts for their prevention and/or therapy.

摘要维生素A对脊椎动物眼睛的重要作用早已为人所知，因为缺乏或过量的维生素A 这种维生素会损害眼睛的发育和功能。维生素A是至少两种关键的代谢物，11-顺式视网膜，视觉G蛋白偶联受体的生色团，以及维甲酸，一种配体对于核受体来说。由于类维甲酸不能由人类从头合成，所以饮食前体必须是被肠道吸收并通过新陈代谢转换。转化后的维甲酸必须运输到在体内储存，并输送到目标组织，如眼睛。这一过程显然取决于特定的转运蛋白和结合蛋白。这些组件最近吸引了广泛的科学和临床兴趣，因为它们与多种疾病有关，如2型糖尿病和致命的马修- 伍德综合征。然而，由于缺乏对这些疾病的研究，我们对这些疾病的病理学知识很少同源哺乳动物动物模型。这样的研究将有助于我们对生物化学的理解维生素A转运的调节机制以及控制维甲酸动态平衡的调节机制。长期的拟议研究的目的是分析影响眼部视黄醇代谢的两个关键步骤：肠道 B，b-胡萝卜素向视黄醇的吸收和代谢转化及b，b-胡萝卜素衍生视黄醇的吸收凝视着他的眼睛。在目标1中，我们将讨论肠道特异的同源异型盒转录因子ISX的作用抑制分别编码类胡萝卜素转运体和密钥的Srb1和Bcmo1基因的活性 B，b-胡萝卜素转化为维甲酸的酶。通过遗传解剖，我们将分析分子基础 B，b-胡萝卜素的吸收和转化为维甲酸以及这一途径的调节。为此，我们将研究isx、srb1和bcmo1单一和复合的b，b-胡萝卜素代谢和维甲酸动态平衡。基因敲除老鼠。将进行启动子/报告基因研究，以阐明这一分子细节调节包括维甲酸在这一过程中的作用。在目标2中，我们将建立缺乏基因敲除小鼠视黄酸刺激的STRA6蛋白研究致死性Matthew-Wood的代谢基础综合症。我们还将产生缺乏STRA6和血清视黄醇结合的复合基因敲除蛋白4(RBP4)，以测试RBP4触发STRA6- 缺乏症。此外，我们还将分析维甲酸在调节血液视黄醇动态平衡中的作用。不同的老鼠突变体。这些研究将为维甲酸代谢和血管紧张素转换酶的控制提供新的见解维甲酸动态平衡将提高对人类疾病状态的理解，这些疾病状态是由并可为其预防和/或治疗提供概念。