Functions of Tocopherol Transfer Protein

生育酚转移蛋白的功能

基本信息

批准号：
7898199
负责人：
DANNY MANOR
金额：
$ 10万
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：
2009-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898199
关键词：
Address Affect Alleles Amino Acids Antioxidants Ataxia Biochemistry Biological Assay Biophysics Brain Brain region Cardiovascular Diseases Catalysis Cells Cellular biology Coupled Cultured Cells Disease Event Fatty acid glycerol esters Gatekeeping Genes Genetic Transcription Goals Health Hepatic Hepatocyte Human Human Pathology In Vitro Indium Lipids Lipoproteins Liver Malignant Neoplasms Maps Mediating Mediator of activation protein Membrane Membrane Lipids Molecular Molecular Profiling Molecular and Cellular Biology Monitor Movement Mutate Mutation Nerve Degeneration Neuraxis Neuronal Dysfunction Neurons Nutrient Optics Organic Chemistry Oxidative Stress Pathology Pattern Peripheral Placenta Plasma Play Population Process Proteins Reaction Recombinants Reporter Role Route Site Structure Synthesis Chemistry Time Tocopherols Travel Variant Vitamin E Vitamin E Deficiency Vitamins alpha-tocopherol transfer protein analog base improved in vivo insight multidisciplinary novel oxidative damage primary outcome promoter protein function public health relevance selective expression skills tissue processing trafficking transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): Vitamin E (tocopherol) is the major fat-soluble antioxidant in humans, and serves a critical function in protection against a plethora of oxidative-stress-related pathologies. However, surprisingly little is known about the molecular mechanisms that regulate the levels and activities of the vitamin in the body. The hepatic alpha tocopherol transfer protein (TTP) is a critical regulator of vitamin E status; humans carrying mutated TTP alleles develop severe vitamin E deficiency, accompanied by neuronal degeneration. TTP is thought to function as a 'gatekeeper' in the liver, where it selectively retains the most biologically active form of vitamin E (RRR-1-tocopherol), and 'directs' it to plasma lipoproteins that deliver the vitamin to peripheral cells. Here, we propose to continue our in vivo and in vitro studies on TTP with the overall goal of understanding the molecular bases for the function of the protein in mediating the effects of vitamin E, both in health and in disease. We will use our combined expertise in synthetic chemistry, biophysics, biochemistry and cell-biology to address four specific aims: 1)- to characterize the steps involved in the transport of vitamin E in hepatocytes, and the exact role of TTP in stimulating this process. Using novel fluorescent analogs of vitamin E, we will monitor the intracellular trafficking of the vitamin in cultured hepatocytes. We will then use molecular- and cell-biology approaches to define the steps that TTP catalyzes, and the molecular mechanisms that underlie these events. 2)- To determine the factors and mechanisms that regulate the expression and degradation of TTP, and the roles that vitamin E status and / or oxidative stress play in these processes. 3)- To examine the functions of TTP in neurons, where the protein is expressed in significant levels, and which are the primary site of damage due to vitamin E deficiency. 4)- To understand the molecular mechanisms by which TTP catalyzes the inter-membrane transfer of vitamin E in vitro. Studies proposed in this application will provide critical information that will improve our understanding of vitamin E function as a mediator of human health. PUBLIC HEALTH RELEVANCE: Vitamin E is an essential nutrient that is required for protection of all cells from oxidative damage. TTP is the only known protein that specifically regulates the levels of vitamin E in the body. We propose to determine what exactly TTP does in liver cells, and how mutations in TTP that are found in humans affect its activity.

描述（由申请人提供）：维生素E（生育酚）是人类中的主要脂溶性抗氧化剂，并且在保护过多的氧化压力相关病理方面具有关键功能。然而，关于调节体内维生素水平和活性的分子机制知之甚少。肝α生育酚转移蛋白（TTP）是维生素E状态的关键调节剂。携带突变TTP等位基因的人类会出现严重的维生素E缺乏症，并伴有神经元变性。 TTP被认为是肝脏中的“守门人”，在该肝脏中，它有选择地保留了维生素E（RRR-1-生育酚）的最活跃形式的形式，并将其“引导”到血浆脂蛋白中，该血浆脂蛋白可将维生素传递到外围细胞。在这里，我们建议继续对TTP进行体内和体外研究，其总体目的是了解蛋白质在介导维生素E在健康和疾病中的作用中的功能的分子碱基。我们将利用合成化学，生物物理学，生物化学和细胞生物学的联合专业知识来解决四个具体目标：1） - 表征维生素E在肝细胞中涉及的步骤，以及TTP在刺激这一过程中的确切作用。使用维生素E的新型荧光类似物，我们将监测培养的肝细胞中维生素的细胞内运输。然后，我们将使用分子和细胞生物学方法来定义TTP催化的步骤以及这些事件构成的分子机制。 2） - 确定调节TTP表达和降解的因素和机制，以及维生素E状态和 /或氧化应激在这些过程中所起的作用。 3） - 检查TTP在神经元中的功能，在神经元中，蛋白质以显着水平表达，并且是由于维生素E缺乏而造成的主要损害部位。 4） - 了解TTP在体外催化维生素E的膜间转移的分子机制。在本应用程序中提出的研究将提供关键信息，以提高我们对维生素E作为人类健康中调解人功能的理解。公共卫生相关性：维生素E是保护所有细胞免受氧化损害所必需的必需营养素。 TTP是唯一专门调节体内维生素E水平的蛋白质。我们建议确定TTP在肝细胞中的确切作用，以及在人类中发现的TTP突变如何影响其活性。