Functions of Tocopherol Transfer Protein

生育酚转移蛋白的功能

• 批准号: 7797517
• 负责人: DANNY MANOR
• 金额: $ 35.65万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797517
• 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

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）是人体内主要的脂溶性抗氧化剂，在预防过多的氧化应激相关病理方面发挥关键作用。然而，令人惊讶的是，人们对调节体内维生素水平和活性的分子机制知之甚少。肝脏α-生育酚转移蛋白（TTP）是维生素E状态的关键调节因子;携带突变TTP等位基因的人发生严重的维生素E缺乏症，伴有神经元变性。TTP被认为是肝脏中的“看门人”，它选择性地保留维生素E（RRR-1-生育酚）的最具生物活性的形式，并将其“引导”到血浆脂蛋白，将维生素传递到外周细胞。在这里，我们建议继续我们的体内和体外研究TTP的总体目标是了解的蛋白质的功能，在介导的维生素E的影响，无论是在健康和疾病的分子基础。我们将利用我们在合成化学，生物物理学，生物化学和细胞生物学方面的综合专业知识来解决四个具体目标：1）-表征肝细胞中维生素E转运所涉及的步骤，以及TTP在刺激这一过程中的确切作用。使用新的维生素E的荧光类似物，我们将监测维生素在培养的肝细胞中的细胞内运输。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，以及这些事件背后的分子机制。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发挥的作用。3)-检查TTP在神经元中的功能，其中蛋白质以显著水平表达，并且是由于维生素E缺乏引起的主要损伤部位。4)-了解TTP在体外催化维生素E膜间转移的分子机制。本申请中提出的研究将提供关键信息，以提高我们对维生素E作为人类健康媒介的理解。公共卫生相关性：维生素E是一种必需的营养素，用于保护所有细胞免受氧化损伤。TTP是唯一已知的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。